Pyrido[3,4-b]indoles and methods of use

ABSTRACT

This disclosure relates to new heterocyclic compounds that may be used to modulate a histamine receptor in an individual. Pyrido[3,4-b]indoles are described, as are pharmaceutical compositions comprising the compounds and methods of using the compounds in a variety of therapeutic applications, including the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 61/039,056 filed Mar. 24, 2008 and U.S. Provisional PatentApplication No. 61/145,079 filed Jan. 15, 2009, the disclosures of eachof which are incorporated herein by reference in their entireties.

STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH

Not applicable.

BACKGROUND OF THE INVENTION

Neurotransmitters such as histamine, serotonin, dopamine andnorepinephrine mediate a large number of processes in the centralnervous system (CNS) as well as outside the CNS. Abnormalneurotransmitter levels are associated with a wide variety of diseasesand conditions including, but not limited to, Alzheimer's disease,Parkinson's Disease, autism, Guillain-Barré syndrome, mild cognitiveimpairment, schizophrenia, anxiety, multiple sclerosis, stroke,traumatic brain injury, spinal cord injury, diabetic neuropathy,fibromyalgia, bipolar disorders, psychosis, depression and a variety ofallergic diseases. Compounds that modulate these neurotransmitters maybe useful therapeutics.

Histamine receptors belong to the superfamily of G protein-coupled seventransmembrane proteins. G protein-coupled receptors constitute one ofthe major signal transduction systems in eukaryotic cells. Codingsequences for these receptors, in those regions believed to contributeto the agonist-antagonist binding site, are strongly conserved acrossmammalian species. Histamine receptors are found in most peripheraltissue and within the central nervous system. Compounds capable ofmodulating a histamine receptor may find use in therapy, e.g., asantihistamines.

Dimebon is a known anti-histamine drug that has also been characterizedas a neuroprotective agent useful to treat, inter alia,neurodegenerative diseases. Dimebon has been shown to inhibit the deathof brain cells (neurons) in preclinical models of Alzheimer's diseaseand Huntington's disease, making it a novel potential treatment forthese and other neurodegenerative diseases. In addition, dimebon hasbeen shown to improve the mitochondrial function of cells in the settingof cellular stress with very high potency. For example, dimebontreatment improved mitochondrial function and increased the number ofsurviving cells after treatment with the cell toxin ionomycin in a dosedependent fashion. Dimebon has also been shown to promote neuriteoutgrowth and neurogenesis, processes important in the formation of newand/or enhanced neuronal cell connections, and evidence of dimebon'spotential for use in additional diseases or conditions. See, e.g., U.S.Pat. Nos. 6,187,785 and 7,071,206 and PCT Patent Application Nos.PCT/US2004/041081, PCT/US2007/020483, PCT/US2006/039077,PCT/US2008/077090, PCT/US2007/020516, PCT/US2007/022645,PCT/US2007/002117, PCT/US2008/006667, PCT/US2007/024626,PCT/US2008/009357, PCT/US2007/024623 and PCT/US2008/008121. Allreferences disclosed herein and throughout, such as publications,patents, patent applications and published patent applications, areincorporated herein by reference in their entireties.

Although dimebon holds great promise as a drug for the treatment ofneurodegenerative diseases and/or diseases in which neurite outgrowthand/or neurogenesis may be implicated in therapy, there remains a needfor new and alternative therapies for the treatment of such diseases orconditions. In addition, there remains a need for new and alternativeantihistamine drugs, preferably ones in which side-effects such asdrowsiness are reduced or eliminated. Compounds that exhibit enhancedand/or more desirable properties than dimebon (e.g., superior safety andefficacy) may find particular use in the treatment of at least thoseindications for which dimebon is believed to be advantageous. Further,compounds that exhibit a different therapeutic profile than dimebon asdetermined, e.g. by in vitro and/or in vivo assays, may find use inadditional diseases and conditions.

BRIEF SUMMARY OF THE INVENTION

Compounds detailed herein are described as histamine receptormodulators. Compositions comprising the compounds are provided, as arekits comprising the compound as well as methods of using and making thecompounds. The compounds may find use in treating neurodegenerativediseases. Compounds of the invention may also find use in treatingdiseases and/or conditions in which modulation of aminergic Gprotein-coupled receptors and/or neurite outgrowth may be implicated intherapy. Compounds disclosed herein may find use the methods disclosedherein, including use in treating, preventing, delaying the onset and/ordelaying the development of a cognitive disorder, psychotic disorder,neurotransmitter-mediated disorder and/or a neuronal disorder in anindividual in need thereof, such as humans.

Compounds of the formula (F) are detailed herein:

wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thioalkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy;

each R¹ and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy or nitro, or R^(2a) andR^(2b) are taken together with the carbon to which they are attached toform a cycloalkyl moiety or a carbonyl moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy, amino, substitutedamino, cycloalkyl, phenyl, acylamino or acyloxy, or R^(3a) and R^(3b)are taken together with the carbon to which they are attached to form acycloalkyl moiety or a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

m and q are independently 0 or 1;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c) and R^(8d) is independently H, hydroxyl,C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, is takentogether with the carbon to which it is attached and a geminalR^(8(a-d)) to form a cycloalkyl moiety or a carbonyl moiety, or is takentogether with a geminal R^(8(a-d)) to form a methylene or a substitutedmethylene;

each R^(10a) and R^(10a) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl, cyano or nitro, or R^(10a)and R^(10b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety or a carbonyl moiety;

R¹¹ and R¹² are independently H or C₁-C₈ alkyl, C₁-C₈ perhaloalkyl,carboxy, carbonylalkoxy, or are taken together with the carbon atoms towhich they are attached to form a substituted or unsubstituted C₃₋₈cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl orsubstituted or unsubstituted heterocyclyl moiety or are taken togetherto form a bond, thereby providing an acetylenyl moiety;

indicates the presence of either an E or Z double bond configurationwhen R¹¹ and R¹² are independently H, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl,carboxy or carbonylalkoxy; and

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or a unsubstituted heterocyclyl,unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl;

or a salt thereof. In one aspect, the salt is a pharmaceuticallyacceptable salt.

Variations of formula (F) are also described, such as where R¹ isunsubstituted C₁-C₈ alkyl and/or Q is phenyl or substituted phenyland/or wherein any one or more of (i)-(xi) apply, provided thatprovisions (iv) and (v) are not combined, provisions (ii) and (xi) arenot combined and provisions (iii) and (xi) are not combined: (i) q and mare both 0; (ii) R¹¹ is H; (iii) R¹² is an unsubstituted C₁-C₈alkyl;(iv) one of R^(3a) and R^(3b) is methyl, ethyl or phenyl and the otheris H; (v) R^(3a) and R^(3b) are both H; (vi) R¹ is an unsubstitutedC₁-C₈ alkyl; (vii) X⁹ is CR⁴ where R⁴ is unsubstituted C₁-C₈ alkyl orhalo; (viii) X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ is H; (ix) R^(2a) andR^(2b) are both H; (x) R^(1a) and R^(10b) are both H; and (xi) R¹¹ andR¹² are taken together to form a bond.

A compound of the formula (E-2) is also described:

wherein:

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy or nitro, or R^(2a) andR^(2b) are taken together with the carbon to which they are attached toform a cycloalkyl moiety or a carbonyl moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy, amino, substitutedamino, cycloalkyl, acylamino or acyloxy or R^(3a) and R^(3b) are takentogether with the carbon to which they are attached to form a cycloalkylmoiety or a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

q is independently 0 or 1;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy,is taken together with the carbon to which it is attached and a geminalR^(8(a-f)) to form a cycloalkyl moiety or a carbonyl moiety, is takentogether with a geminal R^(8(a-f)) to form a methylene or a substitutedmethylene, is taken together with a vicinal R^(8(a-f)) and the carbonatoms to which they are attached to form a substituted or unsubstitutedC₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl orsubstituted or unsubstituted heterocyclyl moiety or is taken togetherwith a vicinal R^(8(a-f)) to form a bond, provided that when anR^(8(a-f)) is taken together with a vicinal R⁸ to form a bond, thegeminal R^(8(a-f)) is other than hydroxyl;

each R^(10a) and R^(10b) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl, cyano or nitro, or R^(1a)and R^(10b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety or a carbonyl moiety;

J is halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, acyl, acyloxy,carbonylalkoxy, thioalkyl, substituted or unsubstituted heterocyclyl,alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino,sulfonyl, carbonyl, aminoacyl and aminocarbonylamino moiety; and

T is an integer from 0 to 5,

or a salt thereof. In one aspect, the salt is a pharmaceuticallyacceptable salt.

Variations of formula (E-2) are also provided, such as when any one ormore of (i)-(viii) apply, provided that only one of (ii), (iii) and (iv)applies: (i) q is 0; (ii) R^(8c) and R^(8d) are both H and R^(8e) andR^(8f) are independently H, hydroxyl or methyl; (iii) R^(8c) is takentogether with R^(8e) to form a bond and R^(8d) is taken together withR^(8f) to form a bond; (iv) one of R^(8c) and R^(8d) is taken togetherwith one of R^(8a) and R^(8f) to form a bond and the R^(8c) or R^(8d)that is not taken to form a bond is H and the R^(8e) or R^(8f) that isnot taken to form a bond is H or methyl; (v) X⁹ is CR⁴ where R⁴ is haloor alkyl; (vi) X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ is H; (vii) R^(2a)and R^(2b) are both H; and (viii) R^(10a) and R^(10b) are both H.

Compound of the formula (E-3) as also embraced:

wherein:

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy or nitro, or R^(2a) andR^(2b) are taken together with the carbon to which they are attached toform a cycloalkyl moiety or a carbonyl moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy, amino, substitutedamino, cycloalkyl, acylamino or acyloxy or R^(3a) and R^(3b) are takentogether with the carbon to which they are attached to form a cycloalkylmoiety or a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

m and q are independently 0 or 1;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy,is taken together with the carbon to which it is attached and a geminalR^(8(a-f)) to form a cycloalkyl moiety or a carbonyl moiety, is takentogether with a geminal R^(8(a-f)) to form a methylene or a substitutedmethylene, is taken together with a vicinal R^(8(a-f)) and the carbonatoms to which they are attached to form a substituted or unsubstitutedC₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl orsubstituted or unsubstituted heterocyclyl moiety or is taken togetherwith a vicinal R^(8(a-f)) to form a bond, provided that when anR^(8(a-f)) is taken together with a vicinal R⁸ to form a bond, thegeminal R^(8(a-f)) is other than hydroxyl;

each R^(10a) and R^(10b) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl, cyano or nitro, or R^(1a)and R^(10b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety or a carbonyl moiety

J is halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, acyl, acyloxy,carbonylalkoxy, thioalkyl, substituted or unsubstituted heterocyclyl,alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino,sulfonyl, carbonyl, aminoacyl and aminocarbonylamino moiety; and

T is an integer from 0 to 4,

or a salt thereof. In one aspect, the salt is a pharmaceuticallyacceptable salt.

Variations of compounds of formula (E-3) are also provided, such as whenany one or more of (i)-(vi) apply, provided that provisions (i) and (ii)are not combined: (i) q is 0; (ii) m and q are each 1 and R^(8c),R^(8d), R^(8e) and R^(8f) are each H; (iii) X⁹ is CR⁴ where R⁴ is haloor substituted or unsubstituted C₁-C₈ alkyl; (iv) X⁷, X⁸ and X¹⁰ areeach CR⁴ where R⁴ is H; (v) R^(2a) and R^(2b) are both H; and (vi)R^(10a) and R^(10b) are both H.

Also described are compounds of the formula (E-4):

wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thioalkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy or nitro, or R^(2a) andR^(2b) are taken together with the carbon to which they are attached toform a cycloalkyl moiety or a carbonyl moiety;

each R^(3a) is H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano,nitro, hydroxyl, alkoxy, amino, substituted amino, cycloalkyl, acylaminoor acyloxy;

X⁹ is N or CR⁴;

q is 0 or 1;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy,is taken together with the carbon to which it is attached and a geminalR^(8(a-f)) to form a cycloalkyl moiety or a carbonyl moiety, is takentogether with a geminal R^(8(a-f)) to form a methylene or a substitutedmethylene, is taken together with a vicinal R^(8(a-f)) and the carbonatoms to which they are attached to form a substituted or unsubstitutedC₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl orsubstituted or unsubstituted heterocyclyl moiety or is taken togetherwith a vicinal R^(8(a-f)) to form a bond, provided that when anR^(8(a-f)) is taken together with a vicinal R⁸ to form a bond, thegeminal R^(8(a-f)) is other than hydroxyl;

each R^(10a) and R^(10b) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl, cyano or nitro, or R^(10a)and R^(10b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety or a carbonyl moiety; and

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or a unsubstituted heterocyclyl,unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl,

or a salt thereof. In one aspect, the salt is a pharmaceuticallyacceptable salt.

Compounds of the formula (E-5) are also provided:

wherein:

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy or nitro, or R^(2a) andR^(2b) are taken together with the carbon to which they are attached toform a cycloalkyl moiety or a carbonyl moiety;

R^(3a) and R^(3b) are independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy, amino, substitutedamino, cycloalkyl, acylamino, phenyl or acyloxy or R^(3a) and R^(3b) aretaken together with the carbon to which they are attached to form acycloalkyl moiety;

X⁹ is CR⁴ where R⁴ is a substituted or unsubstituted C₁-C₈ alkyl orhalo;

q is 0 or 1;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy,is taken together with the carbon to which it is attached and a geminalR^(8(a-f)) to form a cycloalkyl moiety or a carbonyl moiety, is takentogether with a geminal R^(8(a-f)) to form a methylene or a substitutedmethylene, is taken together with a vicinal R^(8(a-f)) and the carbonatoms to which they are attached to form a substituted or unsubstitutedC₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl orsubstituted or unsubstituted heterocyclyl moiety or is taken togetherwith a vicinal R^(8(a-f)) to form a bond, provided that when anR^(8(a-f)) is taken together with a vicinal R⁸ to form a bond, thegeminal R^(8(a-f)) is other than hydroxyl;

each R^(10a) and R^(10b) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl, cyano or nitro, or R^(1a)and R^(10b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety or a carbonyl moiety; and

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or a unsubstituted heterocyclyl,unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl;

or a salt thereof. In one aspect, the salt is a pharmaceuticallyacceptable salt.

Variations of compounds of formula (E-5) are also detailed herein, suchas when any one or more of (i)-(vi) apply, provided that provisions (iv)and (v) are not combined: (i) X⁹ is CR⁴ where R⁴ is an unsubstitutedC₁-C₈ alkyl or halo; (ii) R^(3a) and R^(3b) are independently H orunsubstituted C₁-C₈ alkyl; (iii) R^(2a), R^(2b), R^(10a) and R^(10b) areeach H; (iv) R^(8c) and R^(8d) are taken together to form a carbonyl;(v) one of R^(8c) and R^(8d) is taken together with one of R^(8e) andR^(8f) to form a bond and the R^(8c) or R^(8d) that is not taken to forma bond is H and the R^(8e) or R^(8f) that is not taken to form a bond isa substituted or unsubstituted C₁-C₈ alkyl; and (vi) Q is a substitutedor unsubstituted aryl or substituted or unsubstituted heteroaryl.

Compounds of the formula (E-6) are provided:

wherein:

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy or nitro, or R^(2a) andR^(2b) are taken together with the carbon to which they are attached toform a cycloalkyl moiety or a carbonyl moiety;

R^(3a) and R^(3b) are independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy, amino, substitutedamino, cycloalkyl, phenyl, acylamino or acyloxy or R^(3a) and R^(3b) aretaken together with the carbon to which they are attached to form acycloalkyl moiety;

each X⁷, X⁸ and X¹⁰ is independently N or CR⁴;

X⁹ is N or CR⁴ where R⁴ is halo or a substituted or unsubstituted C₁-C₈alkyl;

m and q are independently 0 or 1;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy,is taken together with the carbon to which it is attached and a geminalR^(8(a-f)) to form a cycloalkyl moiety or a carbonyl moiety, is takentogether with a geminal R^(8(a-f)) to form a methylene or a substitutedmethylene, is taken together with a vicinal R^(8(a-f)) and the carbonatoms to which they are attached to form a substituted or unsubstitutedC₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl orsubstituted or unsubstituted heterocyclyl moiety or is taken togetherwith a vicinal R^(8(a-f)) to form a bond, provided that when anR^(8(a-f)) is taken together with a vicinal R⁸ to form a bond, thegeminal R^(8(a-f)) is other than hydroxyl;

each R^(10a) and R^(10b) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl, cyano or nitro, or R^(1a)and R^(10b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety or a carbonyl moiety;

Q comprises a substituted phenyl, unsubstituted phenyl, substitutedpyridyl or unsubstituted pyridyl moiety,

or a salt thereof. In one aspect, the salt is a pharmaceuticallyacceptable salt.

Variations of compounds of the formula (E-6) are detailed herein, suchas when any one or more of (i)-(ix) apply, provided that when one ofprovisions (iv), (v) or (vi) apply, only one of provisions (iv), (v) or(vi) applies: (i) X⁹ is CR⁴ where R⁴ is an unsubstituted C₁-C₈ alkyl orhalo; (ii) R^(3a) and R^(3b) are independently H, phenyl orunsubstituted C₁-C₈ alkyl; (iii) R^(2a), R^(2b), R^(10a) and R^(10b) areeach H; (iv) m is 1 and R^(8c) and R^(8d) are taken together to form acarbonyl; (v) m is 1 and one of R^(8c) and R^(8d) is taken together withone of R^(8e) and R^(8f) to form a bond and the R^(8c) or R^(8d) that isnot taken to form a bond is H and the R^(8a) or R^(8f) that is not takento form a bond is a substituted or unsubstituted C₁-C₈ alkyl or H; (vi)m is 1 and R^(8c) is taken together with R^(8e) to form a bond andR^(8d) is taken together with R^(8f) to form a bond; (vii) q is 0;(viii) X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ is H; and (ix) Q is asubstituted or unsubstituted phenyl or pyridyl moiety.

Compounds of the formula (E-7) are also embraced:

wherein:

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy or nitro, or R^(2a) andR^(2b) are taken together with the carbon to which they are attached toform a cycloalkyl moiety or a carbonyl moiety;

R^(3a) and R^(3b) are independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy, amino, substitutedamino, cycloalkyl, phenyl, acylamino or acyloxy or R^(3a) and R^(3b) aretaken together with the carbon to which they are attached to form acycloalkyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

q is 0 or 1;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy,is taken together with the carbon to which it is attached and a geminalR^(8(a-f)) to form a cycloalkyl moiety or a carbonyl moiety, is takentogether with a geminal R^(8(a-f)) to form a methylene or a substitutedmethylene, is taken together with a vicinal R^(8(a-f)) and the carbonatoms to which they are attached to form a substituted or unsubstitutedC₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl orsubstituted or unsubstituted heterocyclyl moiety or is taken togetherwith a vicinal R^(8(a-f)) to form a bond, provided that when anR^(8(a-f)) is taken together with a vicinal R⁸ to form a bond, thegeminal R^(8(a-f)) is other than hydroxyl;

each R^(10a) and R^(10b) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl, cyano or nitro, or R^(1a)and R^(10b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety or a carbonyl moiety;

Q is an unsubstituted cycloalkyl, substituted cycloalkyl, unsubstitutedheterocyclyl or substituted heterocyclyl moiety,

or a salt thereof. In one aspect, the salt is a pharmaceuticallyacceptable salt.

Variations of compounds of the formula (E-7) are also provided, such aswhen any one or more of (i)-(viii) applies, provided that provisions(iv) and (v) are not combined: (i) X⁹ is CR⁴ where R⁴ is H, anunsubstituted C₁-C₈ alkyl or halo; (ii) R^(3a) and R^(3b) are each H;(iii) R^(2a), R^(2b), R^(10a) and R^(10b) are each H; (iv) R^(8e) andR^(8f) are taken together to form a carbonyl; (v) R^(8c), R^(8d), R^(8e)and R^(8f) are each H; (vi) q is 0; (vii) X⁷, X⁸ and X¹⁰ are each CR⁴where R⁴ is H; and (viii) Q is a substituted or unsubstitutedcyclopentyl, cyclohexyl, piperidinyl or piperazinyl moiety.

Further compounds include those of the formula (E-8):

wherein:

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy or nitro, or R^(2a) andR^(2b) are taken together with the carbon to which they are attached toform a cycloalkyl moiety or a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

m is 0 or 1;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy,is taken together with the carbon to which it is attached and a geminalR^(8(a-f)) to form a cycloalkyl moiety or a carbonyl moiety, is takentogether with a geminal R^(8(a-f)) to form a methylene or a substitutedmethylene, is taken together with a vicinal R^(8(a-f)) and the carbonatoms to which they are attached to form a substituted or unsubstitutedC₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl orsubstituted or unsubstituted heterocyclyl moiety or is taken togetherwith a vicinal R^(8(a-f)) to form a bond, provided that when anR^(8(a-f)) is taken together with a vicinal R⁸ to form a bond, thegeminal R^(8(a-f)) is other than hydroxyl;

each R^(10a) and R^(10b) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl, cyano or nitro, or R^(10a)and R^(10b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety or a carbonyl moiety;

Q is unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl,

or a salt thereof. In one aspect, the salt is a pharmaceuticallyacceptable salt.

Additional compounds are provided, including compounds of the formula(E) as detailed herein and any variation thereof.

The invention also includes all salts of compounds referred to herein,such as pharmaceutically acceptable salts. The invention also includesany or all of the stereochemical forms, including any enantiomeric ordiastereomeric forms, of the compounds described. Unless stereochemistryis explicitly indicated in a chemical structure or name, the structureor name is intended to embrace all possible stereoisomers of a compounddepicted. All forms of the compounds are also embraced by the invention,such as crystalline or non-crystalline forms of the compounds.Compositions comprising a compound of the invention are also intended,such as a composition of substantially pure compound, including aspecific stereochemical form thereof. Compositions comprising a mixtureof compounds of the invention in any ratio are also embraced by theinvention, including mixtures of two or more stereochemical forms of acompound of the invention in any ratio, such that racemic, non-racemic,enantioenriched and scalemic mixtures of a compound are embraced.

The invention is also directed to pharmaceutical compositions comprisinga compound of the invention and a pharmaceutically acceptable carrier orexcipient. Kits comprising a compound of the invention and instructionsfor use are also embraced by this invention. Compounds as detailedherein or a pharmaceutically acceptable salt thereof are also providedfor the manufacture of a medicament for the treatment of a cognitivedisorder, psychotic disorder, neurotransmitter-mediated disorder or aneuronal disorder.

In one aspect, compounds of the invention are used to treat, prevent,delay the onset and/or delay the development of any one or more of thefollowing: cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders inindividuals in need thereof, such as humans. In one variation, compoundsof the invention are used to treat, prevent, delay the onset and/ordelay the development of diseases or conditions for which the modulationof an aminergic G protein-coupled receptor is believed to be or isbeneficial. In one variation, compounds of the invention are used totreat, prevent, delay the onset and/or delay the development of any oneor more of diseases or conditions for which neurite outgrowth and/orneurogenesis and/or neurotrophic effects are believed to be or arebeneficial. In another variation, compounds of the invention are used totreat, prevent, delay the onset and/or delay the development of diseasesor conditions for which the modulation of an aminergic G protein-coupledreceptor and neurite outgrowth and/or neurogenesis and/or neurotrophiceffects are believed to be or are beneficial. In one variation, thedisease or condition is a cognitive disorder, psychotic disorder,neurotransmitter-mediated disorder and/or a neuronal disorder.

In another aspect, compounds of the invention are used to improvecognitive function and/or reduce psychotic effects in an individual,comprising administering to an individual in need thereof an amount of acompound described herein or a pharmaceutically acceptable salt thereofeffective to improve cognitive function and/or reduce psychotic effects.

In a further aspect, compounds of the invention are used to stimulateneurite outgrowth and/or promote neurogenesis and/or enhanceneurotrophic effects in an individual comprising administering to anindividual in need thereof an amount of a compound described herein or apharmaceutically acceptable salt thereof effective to stimulate neuriteoutgrowth and/or to promote neurogenesis and/or to enhance neurotrophiceffects. Synapse loss is associated with a variety of neurodegenerativediseases and conditions including Alzheimer's disease, Huntington'sdisease, Parkinson's disease, amyotrophic lateral sclerosis, stroke,head trauma and spinal cord injury. Compounds of the invention thatstimulate neurite outgrowth may have a benefit in these settings.

In another aspect, compounds described herein are used to modulate anaminergic G protein-coupled receptor comprising administering to anindividual in need thereof an amount of a compound described herein or apharmaceutically acceptable salt thereof effective to modulate anaminergic G protein-coupled receptor. In one variation, a compound ofthe invention modulates at least one of the following receptors:adrenergic receptor (e.g., α1D, α2A and/or α2B), serotonin receptor(e.g., 5-HT2A, 5-HT2C, 5-HT6 and/or 5-HT7), dopamine receptor (e.g.,D2L) and histamine receptor (e.g., H1, H2 and/or H3). In anothervariation, at least two of the following receptors are modulated:adrenergic receptor (e.g., α1D, α2A and/or α2B), serotonin receptor(e.g., 5-HT2A, 5-HT2C, 5-HT6 and/or 5-HT7), dopamine receptor (e.g.,D2L) and histamine receptor (e.g., H1, H2 and/or H3). In anothervariation, at least three of the following receptors are modulated:adrenergic receptor (e.g., α1D, α2A and/or α2B), serotonin receptor(e.g., 5-HT2A, 5-HT2C, 5-HT6 and/or 5-HT7), dopamine receptor (e.g.,D2L) and histamine receptor (e.g., H1, H2 and/or H3). In anothervariation, each of the following receptors is modulated: adrenergicreceptor (e.g., α1D, α2A and/or α2B), serotonin receptor (e.g., 5-HT2A,5-HT2C, 5-HT6 and/or 5-HT7), dopamine receptor (e.g., D2L) and histaminereceptor (e.g., H1, H2 and/or H3). In another variation, at least one ofthe following receptors is modulated: α1D, α2A, α2B, 5-HT2A, 5-HT2C,5-HT6, 5-HT7, D2L, H1, H2 and H3. In another variation, at least two orthree or four or five or six or seven or eight or nine or ten or elevenof the following receptors are modulated: α1D, α2A, α2B, 5-HT2A, 5-HT2C,5-HT6, 5-HT7, D2L, H1, H2 and H3. In a particular variation, at leastdopamine receptor D2L is modulated. In another particular variation, atleast dopamine receptor D2L and serotonin receptor 5-HT2A are modulated.In a further particular variation, at least adrenergic receptors α1D,α2A, α2B and serotonin receptor 5-HT6 are modulated. In anotherparticular variation, at least adrenergic receptors α1D, α2A, α2B,serotonin receptor 5-HT6 and one or more of serotonin receptor 5-HT7,5-HT2A, 5-HT2C and histamine receptor H1 and H2 are modulated. In afurther particular variation, histamine receptor H1 is modulated. Inanother variation, compounds of the invention exhibit any receptormodulation activity detailed herein and further stimulate neuriteoutgrowth and/or neurogenesis and/or enhance neurotrophic effects.

The invention is also directed to pharmaceutical compositions comprisinga compound of the invention and a pharmaceutically acceptable carrier orexcipient. Kits comprising a compound of the invention and instructionsfor use are also embraced by this invention.

DETAILED DESCRIPTION OF THE INVENTION Definitions

For use herein, unless clearly indicated otherwise, use of the terms“a”, “an” and the like refers to one or more.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”.

As used herein, the term “adrenergic receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toan adrenergic receptor or reduces or eliminates or increases or enhancesor mimics an activity of an adrenergic receptor. As such, an “adrenergicreceptor modulator” encompasses both an adrenergic receptor antagonistand an adrenergic receptor agonist. In some aspects, the adrenergicreceptor modulator binds to or inhibits binding to a ligand to anα1-adrenergic receptor (e.g., α1A, α1B and/or α1D) and/or aα2-adrenergic receptor (e.g., α2A, α2B and/or α2C) and/or reduces oreliminates or increases or enhances or mimics an activity of aα1-adrenergic receptor (e.g., α1A, α1B and/or α1D) and/or aα2-adrenergic receptor (e.g., α2A, α2B and/or α2C) in a reversible orirreversible manner. In some aspects, the adrenergic receptor modulatorinhibits binding of a ligand by at least about or about any one of 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in theassays described herein. In some aspects, the adrenergic receptormodulator reduces an activity of an adrenergic receptor by at least orabout any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% ascompared to the corresponding activity in the same subject prior totreatment with the adrenergic receptor modulator or compared to thecorresponding activity in other subjects not receiving the adrenergicreceptor modulator. In some aspects, the adrenergic receptor modulatorenhances an activity of an adrenergic receptor by at least about orabout any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or200% or 300% or 400% or 500% or more as compared to the correspondingactivity in the same subject prior to treatment with the adrenergicreceptor modulator or compared to the corresponding activity in othersubjects not receiving the adrenergic receptor modulator. In someaspects, the adrenergic receptor modulator is capable of binding to theactive site of an adrenergic receptor (e.g., a binding site for aligand). In some embodiments, the adrenergic receptor modulator iscapable of binding to an allosteric site of an adrenergic receptor.

As used herein, the term “dopamine receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toa dopamine receptor or reduces or eliminates or increases or enhances ormimics an activity of a dopamine receptor. As such, a “dopamine receptormodulator” encompasses both a dopamine receptor antagonist and adopamine receptor agonist. In some aspects, the dopamine receptormodulator binds to or inhibits binding of a ligand to a dopamine-1 (D1)and/or a dopamine-2 (D2) receptor or reduces or eliminates or increasesor enhances or mimics an activity of a dopamine-1 (D1) and/or adopamine-2 (D2) receptor in a reversible or irreversible manner.Dopamine D2 receptors are divided into two categories, D2L and D2S,which are formed from a single gene by differential splicing. D2Lreceptors have a longer intracellular domain than D2S. In someembodiments, the dopamine receptor modulator inhibits binding of aligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 95% or 100% as determined in the assays describedherein. In some embodiments, the dopamine receptor modulator reduces anactivity of a dopamine receptor by at least about or about any of 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to thecorresponding activity in the same subject prior to treatment with thedopamine receptor modulator or compared to the corresponding activity inother subjects not receiving the dopamine receptor modulator. In someembodiments, the dopamine receptor modulator enhances an activity of adopamine receptor by at least about or about any of 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% ormore as compared to the corresponding activity in the same subject priorto treatment with the dopamine receptor modulator or compared to thecorresponding activity in other subjects not receiving the dopaminereceptor modulator. In some embodiments, the dopamine receptor modulatoris capable of binding to the active site of a dopamine receptor (e.g., abinding site for a ligand). In some embodiments, the dopamine receptormodulator is capable of binding to an allosteric site of a dopaminereceptor.

As used herein, the term “serotonin receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toa serotonin receptor or reduces or eliminates or increases or enhancesor mimics an activity of a serotonin receptor. As such, a “serotoninreceptor modulator” encompasses both a serotonin receptor antagonist anda serotonin receptor agonist. In some embodiments, the serotoninreceptor modulator binds to or inhibits binding of a ligand to a 5-HT1Aand/or a 5-HT1B and/or a 5-HT2A and/or a 5-HT2B and/or a 5-HT2C and/or a5-HT3 and/or a 5-HT4 and/or a 5-HT6 and/or a 5-HT7 receptor or reducesor eliminates or increases or enhances or mimics an activity of a 5-HT1Aand/or a 5-HT1B and/or a 5-HT2A and/or a 5-HT2B and/or a 5-HT2C and/or a5-HT3 and/or a 5-HT4 and/or a 5-HT6 and/or a 5-HT7 receptor in areversible or irreversible manner. In some embodiments, the serotoninreceptor modulator inhibits binding of a ligand by at least about orabout any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or100% as determined in the assays described herein. In some embodiments,the serotonin receptor modulator reduces an activity of a serotoninreceptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95% or 100% as compared to the corresponding activity inthe same subject prior to treatment with the serotonin receptormodulator or compared to the corresponding activity in other subjectsnot receiving the serotonin receptor modulator. In some embodiments, theserotonin receptor modulator enhances an activity of a serotoninreceptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% or more ascompared to the corresponding activity in the same subject prior totreatment with the serotonin receptor modulator or compared to thecorresponding activity in other subjects not receiving the serotoninreceptor modulator. In some embodiments, the serotonin receptormodulator is capable of binding to the active site of a serotoninreceptor (e.g., a binding site for a ligand). In some embodiments, theserotonin receptor modulator is capable of binding to an allosteric siteof a serotonin receptor.

As used herein, the term “histamine receptor modulator” intends andencompasses a compound that reduces or eliminates or increases orenhances an activity of a histamine receptor. As such, a “histaminereceptor modulator” encompasses both a histamine receptor antagonist anda histamine receptor agonist. In some embodiments, the histaminereceptor modulator reduces or eliminates or increases or enhances anactivity of a histamine receptor in a reversible or irreversible manner.In some embodiments, the histamine receptor modulator reduces anactivity of a histamine receptor by at least or about any of 10%, 20%,30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to thecorresponding activity in the same individual prior to treatment withthe histamine receptor modulator or compared to the correspondingactivity in like individuals not receiving the histamine receptormodulator. In some embodiments, the histamine receptor modulatorenhances an activity of a histamine receptor by at least or about any of10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300%or 400% or 500% or more as compared to the corresponding activity in thesame individual prior to treatment with the histamine receptor modulatoror compared to the corresponding activity in like individuals notreceiving the histamine receptor modulator. In some embodiments, thehistamine receptor modulator is capable of binding to the active site ofa histamine receptor (e.g., a binding site for a ligand). In someembodiments, the histamine receptor modulator is capable of binding toan allosteric site of a histamine receptor.

Unless clearly indicated otherwise, “an individual” as used hereinintends a mammal, including but not limited to a human. An individualincludes but is not limited to human, bovine, primate, equine, canine,feline, porcine, and ovine animals. Thus, the invention finds use inboth human medicine and in the veterinary context, including use inagricultural animals and domestic pets. The individual may be a humanwho has been diagnosed with or is suspected of having a cognitivedisorder, a psychotic disorder, a neurotransmitter-mediated disorderand/or a neuronal disorder. The individual may be a human who exhibitsone or more symptoms associated with a cognitive disorder, a psychoticdisorder, a neurotransmitter-mediated disorder and/or a neuronaldisorder. The individual may be a human who has a mutated or abnormalgene associated with a cognitive disorder, a psychotic disorder, aneurotransmitter-mediated disorder and/or a neuronal disorder. Theindividual may be a human who is genetically or otherwise predisposed todeveloping a cognitive disorder, a psychotic disorder, aneurotransmitter-mediated disorder and/or a neuronal disorder.

As used herein, “treatment” or “treating” is an approach for obtaining abeneficial or desired result, such as a clinical result.

For purposes of this invention, beneficial or desired clinical resultsinclude, but are not limited to, alleviation of a symptom and/ordiminishment of the extent of a symptom and/or preventing a worsening ofa symptom associated with a disease or condition. In one variation,beneficial or desired clinical results include, but are not limited to,alleviation of a symptom and/or diminishment of the extent of a symptomand/or preventing a worsening of a symptom associated with a cognitivedisorder, a psychotic disorder, a neurotransmitter-mediated disorderand/or a neuronal disorder. Preferably, treatment of a disease orcondition with a compound of the invention or a pharmaceuticallyacceptable salt thereof is accompanied by no or fewer side effects thanare associated with currently available therapies for the disease orcondition and/or improves the quality of life of the individual.

As used herein, “delaying” development of a disease or condition meansto defer, hinder, slow, retard, stabilize and/or postpone development ofthe disease or condition. This delay can be of varying lengths of time,depending on the history of the disease and/or individual being treated.As is evident to one skilled in the art, a sufficient or significantdelay can, in effect, encompass prevention, in that the individual doesnot develop the disease or condition. For example, a method that“delays” development of Alzheimer's disease is a method that reducesprobability of disease development in a given time frame and/or reducesextent of the disease in a given time frame, when compared to not usingthe method. Such comparisons are typically based on clinical studies,using a statistically significant number of subjects. For example,Alzheimer's disease development can be detected using standard clinicaltechniques, such as routine neurological examination, patient interview,neuroimaging, detecting alterations of levels of specific proteins inthe serum or cerebrospinal fluid (e.g., amyloid peptides and Tau),computerized tomography (CT) or magnetic resonance imaging (MRI).Similar techniques are known in the art for other diseases andconditions. Development may also refer to disease progression that maybe initially undetectable and includes occurrence, recurrence and onset.

As used herein, an “at risk” individual is an individual who is at riskof developing a cognitive disorder, a psychotic disorder, aneurotransmitter-mediated disorder and/or a neuronal disorder that canbe treated with a compound of the invention. An individual “at risk” mayor may not have a detectable disease or condition, and may or may nothave displayed detectable disease prior to the treatment methodsdescribed herein. “At risk” denotes that an individual has one or moreso-called risk factors, which are measurable parameters that correlatewith development of a disease or condition and are known in the art. Anindividual having one or more of these risk factors has a higherprobability of developing the disease or condition than an individualwithout these risk factor(s). These risk factors include, but are notlimited to, age, sex, race, diet, history of previous disease, presenceof precursor disease, genetic (i.e., hereditary) considerations, andenvironmental exposure. For example, individuals at risk for Alzheimer'sdisease include, e.g., those having relatives who have experienced thisdisease and those whose risk is determined by analysis of genetic orbiochemical markers. Genetic markers of risk for Alzheimer's diseaseinclude mutations in the APP gene, particularly mutations at position717 and positions 670 and 671 referred to as the Hardy and Swedishmutations, respectively (Hardy, Trends Neurosci., 20:154-9, 1997). Othermarkers of risk are mutations in the presenilin genes (e.g., PS1 orPS2), ApoE4 alleles, family history of Alzheimer's disease,hypercholesterolemia and/or atherosclerosis. Other such factors areknown in the art for other diseases and conditions.

As used herein, the term “pro-cognitive” includes but is not limited toan improvement of one or more mental processes such as memory,attention, perception and/or thinking, which may be assessed by methodsknown in the art.

As used herein, the term “neurotrophic” effects includes but is notlimited to effects that enhance neuron function such as growth, survivaland/or neurotransmitter synthesis.

As used herein, the term “cognitive disorders” refers to and intendsdiseases and conditions that are believed to involve or be associatedwith or do involve or are associated with progressive loss of structureand/or function of neurons, including death of neurons, and where acentral feature of the disorder may be the impairment of cognition(e.g., memory, attention, perception and/or thinking). These disordersinclude pathogen-induced cognitive dysfunction, e.g. HIV associatedcognitive dysfunction and Lyme disease associated cognitive dysfunction.Examples of cognitive disorders include Alzheimer's Disease,Huntington's Disease, Parkinson's Disease, schizophrenia, amyotrophiclateral sclerosis (ALS), autism, mild cognitive impairment (MC1),stroke, traumatic brain injury (TBI) and age-associated memoryimpairment (AAMI).

As used herein, the term “psychotic disorders” refers to and intendsmental diseases or conditions that are believed to cause or do causeabnormal thinking and perceptions. Psychotic disorders are characterizedby a loss of reality which may be accompanied by delusions,hallucinations (perceptions in a conscious and awake state in theabsence of external stimuli which have qualities of real perception, inthat they are vivid, substantial, and located in external objectivespace), personality changes and/or disorganized thinking. Other commonsymptoms include unusual or bizarre behavior, as well as difficulty withsocial interaction and impairment in carrying out the activities ofdaily living. Exemplary psychotic disorders are schizophrenia, bipolardisorders, psychosis, anxiety and depression.

As used herein, the term “neurotransmitter-mediated disorders” refers toand intends diseases or conditions that are believed to involve or beassociated with or do involve or are associated with abnormal levels ofneurotransmitters such as histamine, serotonin, dopamine, norepinephrineor impaired function of aminergic G protein-coupled receptors. Exemplaryneurotransmitter-mediated disorders include spinal cord injury, diabeticneuropathy, allergic diseases and diseases involving geroprotectiveactivity such as age-associated hair loss (alopecia), age-associatedweight loss and age-associated vision disturbances (cataracts). Abnormalneurotransmitter levels are associated with a wide variety of diseasesand conditions including, but not limited, to Alzheimer's disease,Parkinson's Disease, autism, Guillain-Barré syndrome, mild cognitiveimpairment, schizophrenia, anxiety, multiple sclerosis, stroke,traumatic brain injury, spinal cord injury, diabetic neuropathy,fibromyalgia, bipolar disorders, psychosis, depression and a variety ofallergic diseases.

As used herein, the term “neuronal disorders” refers to and intendsdiseases or conditions that are believed to involve, or be associatedwith, or do involve or are associated with neuronal cell death and/orimpaired neuronal function or decreased neuronal function. Exemplaryneuronal indications include neurodegenerative diseases and disorderssuch as Alzheimer's disease, Huntington's disease, amyotrophic lateralsclerosis (ALS), Parkinson's disease, canine cognitive dysfunctionsyndrome (CCDS), Lewy body disease, Menkes disease, Wilson disease,Creutzfeldt-Jakob disease, Fahr disease, an acute or chronic disorderinvolving cerebral circulation, such as ischemic or hemorrhagic strokeor other cerebral hemorrhagic insult, age-associated memory impairment(AAMI), mild cognitive impairment (MC1), injury-related mild cognitiveimpairment (MC1), post-concussion syndrome, post-traumatic stressdisorder, adjuvant chemotherapy, traumatic brain injury (TBI), neuronaldeath mediated ocular disorder, macular degeneration, age-relatedmacular degeneration, autism, including autism spectrum disorder,Asperger syndrome, and Rett syndrome, an avulsion injury, a spinal cordinjury, myasthenia gravis, Guillain-Barré syndrome, multiple sclerosis,diabetic neuropathy, fibromyalgia, neuropathy associated with spinalcord injury, schizophrenia, bipolar disorder, psychosis, anxiety ordepression.

As used herein, the term “neuron” represents a cell of ectodermalembryonic origin derived from any part of the nervous system of ananimal. Neurons express well-characterized neuron-specific markers,including neurofilament proteins, NeuN (Neuronal Nuclei marker), MAP2,and class III tubulin. Included as neurons are, for example,hippocampal, cortical, midbrain dopaminergic, spinal motor, sensory,sympathetic, septal cholinergic, and cerebellar neurons.

As used herein, the term “neurite outgrowth” or “neurite activation”refers to the extension of existing neuronal processes (e.g., axons anddendrites) and the growth or sprouting of new neuronal processes (e.g.,axons and dendrites). Neurite outgrowth or neurite activation may alterneural connectivity, resulting in the establishment of new synapses orthe remodeling of existing synapses.

As used herein, the term “neurogenesis” refers to the generation of newnerve cells from undifferentiated neuronal progenitor cells, also knownas multipotential neuronal stem cells. Neurogenesis actively producesnew neurons, astrocytes, glia, Schwann cells, oligodendrocytes and/orother neural lineages. Much neurogenesis occurs early in humandevelopment, though it continues later in life, particularly in certainlocalized regions of the adult brain.

As used herein, the term “neural connectivity” refers to the number,type, and quality of connections (“synapses”) between neurons in anorganism. Synapses form between neurons, between neurons and muscles (a“neuromuscular junction”), and between neurons and other biologicalstructures, including internal organs, endocrine glands, and the like.Synapses are specialized structures by which neurons transmit chemicalor electrical signals to each other and to non-neuronal cells, muscles,tissues, and organs. Compounds that affect neural connectivity may do soby establishing new synapses (e.g., by neurite outgrowth or neuriteactivation) or by altering or remodeling existing synapses. Synapticremodeling refers to changes in the quality, intensity or type of signaltransmitted at particular synapses.

As used herein, the term “neuropathy” refers to a disorder characterizedby altered function and/or structure of motor, sensory, and autonomicneurons of the nervous system, initiated or caused by a primary lesionor other dysfunction of the nervous system. Patterns of peripheralneuropathy include polyneuropathy, mononeuropathy, mononeuritismultiplex and autonomic neuropathy. The most common form is(symmetrical) peripheral polyneuropathy, which mainly affects the feetand legs. A radiculopathy involves spinal nerve roots, but if peripheralnerves are also involved the term radiculoneuropathy is used. The formof neuropathy may be further broken down by cause, or the size ofpredominant fiber involvement, e.g. large fiber or small fiberperipheral neuropathy. Central neuropathic pain can occur in spinal cordinjury, multiple sclerosis, and some strokes, as well as fibromyalgia.Neuropathy may be associated with varying combinations of weakness,autonomic changes and sensory changes. Loss of muscle bulk orfasciculations, a particular fine twitching of muscle may also be seen.Sensory symptoms encompass loss of sensation and “positive” phenomenaincluding pain. Neuropathies are associated with a variety of disorders,including diabetes (e.g., diabetic neuropathy), fibromyalgia, multiplesclerosis, and herpes zoster infection, as well as with spinal cordinjury and other types of nerve damage.

As used herein, the term “Alzheimer's disease” refers to a degenerativebrain disorder characterized clinically by progressive memory deficits,confusion, behavioral problems, inability to care for oneself, gradualphysical deterioration and, ultimately, death. Histologically, thedisease is characterized by neuritic plaques, found primarily in theassociation cortex, limbic system and basal ganglia. The majorconstituent of these plaques is amyloid beta peptide (Aβ), which is thecleavage product of beta amyloid precursor protein (βAPP or APP). APP isa type I transmembrane glycoprotein that contains a large ectopicN-terminal domain, a transmembrane domain and a small cytoplasmicC-terminal tail. Alternative splicing of the transcript of the singleAPP gene on chromosome 21 results in several isoforms that differ in thenumber of amino acids. Aβ appears to have a central role in theneuropathology of Alzheimer's disease. Familial forms of the diseasehave been linked to mutations in APP and the presenilin genes (Tanzi etal., 1996, Neurobiol. Dis., 3:159-168; Hardy, 1996, Ann. Med.,28:255-258). Diseased-linked mutations in these genes result inincreased production of the 42-amino acid form of Aβ, the predominantform found in amyloid plaques. Mitochondrial dysfunction has also beenreported to be an important component of Alzheimer's disease (Bubber etal., Mitochondrial abnormalities in Alzheimer brain: MechanisticImplications, Ann Neurol., 2005, 57(5), 695-703; Wang et al., Insightsinto amyloid-β-induced mitochondrial dysfunction in Alzheimer disease,Free Radical Biology & Medicine, 2007, 43, 1569-1573; Swerdlow et al.,Mitochondria in Alzheimer's disease, Int. Rev. Neurobiol., 2002, 53,341-385; and Reddy et al., Are mitochondria critical in the pathogenesisof Alzheimer's disease?, Brain Res Rev. 2005, 49(3), 618-32). It hasbeen proposed that mitochondrial dysfunction has a causal relationshipwith neuronal function (including neurotransmitter synthesis andsecretion) and viability. Compounds which stabilize mitochondria maytherefore have a beneficial impact on Alzheimer's patients.

As used herein, the term “Huntington's disease” refers to a fatalneurological disorder characterized clinically by symptoms such asinvoluntary movements, cognition impairment or loss of cognitivefunction and a wide spectrum of behavioral disorders. Common motorsymptoms associated with Huntington's disease include chorea(involuntary writhing and spasming), clumsiness, and progressive loss ofthe abilities to walk, speak (e.g., exhibiting slurred speech) andswallow. Other symptoms of Huntington's disease can include cognitivesymptoms such as loss of intellectual speed, attention and short-termmemory and/or behavioral symptoms that can span the range of changes inpersonality, depression, irritability, emotional outbursts and apathy.Clinical symptoms typically appear in the fourth or fifth decade oflife. Huntington's disease is a devastating and often protractedillness, with death usually occurring approximately 10-20 years afterthe onset of symptoms. Huntington's disease is inherited through amutated or abnormal gene encoding an abnormal protein called the mutanthuntingtin protein; the mutated huntingtin protein produces neuronaldegeneration in many different regions of the brain. The degenerationfocuses on neurons located in the basal ganglia, structures deep withinthe brain that control many important functions including coordinatingmovement, and on neurons on the outer surface of the brain or cortex,which controls thought, perception and memory.

“Amyotrophic lateral sclerosis” or “ALS” is used herein to denote aprogressive neurodegenerative disease that affects upper motor neurons(motor neurons in the brain) and/or lower motor neurons (motor neuronsin the spinal cord) and results in motor neuron death. As used herein,the term “ALS” includes all of the classifications of ALS known in theart, including, but not limited to classical ALS (typically affectingboth lower and upper motor neurons), Primary Lateral Sclerosis (PLS,typically affecting only the upper motor neurons), Progressive BulbarPalsy (PBP or Bulbar Onset, a version of ALS that typically begins withdifficulties swallowing, chewing and speaking), Progressive MuscularAtrophy (PMA, typically affecting only the lower motor neurons) andfamilial ALS (a genetic version of ALS).

The term “Parkinson's disease” as used herein refers to any medicalcondition wherein an individual experiences one or more symptomsassociated with Parkinson's disease, such as without limitation one ormore of the following symptoms: rest tremor, cogwheel rigidity,bradykinesia, postural reflex impairment, symptoms having good responseto 1-dopa treatment, the absence of prominent oculomotor palsy,cerebellar or pyramidal signs, amyotrophy, dyspraxia and/or dysphasia.In a specific embodiment, the present invention is utilized for thetreatment of a dopaminergic dysfunction-related disorder. In a specificembodiment, the individual with Parkinson's disease has a mutation orpolymorphism in a synuclein, parkin or NURR1 nucleic acid that isassociated with Parkinson's disease. In one embodiment, the individualwith Parkinson's disease has defective or decreased expression of anucleic acid or a mutation in a nucleic acid that regulates thedevelopment and/or survival of dopaminergic neurons.

As used herein, the term “canine cognitive dysfunction syndrome,” or“CCDS” refers to an age-related deterioration of mental functiontypified by multiple cognitive impairments that affect an afflictedcanine's ability to function normally. The decline in cognitive abilitythat is associated with CCDS cannot be completely attributed to ageneral medical condition such as neoplasia, infection, sensoryimpairment, or organ failure. Diagnosis of CCDS in canines, such asdogs, is generally a diagnosis of exclusion, based on thorough behaviorand medical histories and the presence of clinical symptoms of CCDS thatare unrelated to other disease processes. Owner observation ofage-related changes in behavior is a practical means used to detect thepossible onset of CCDS in aging domestic dogs. A number of laboratorycognitive tasks may be used to help diagnose CCDS, while blood counts,chemistry panels and urinalysis can be used to rule out other underlyingdiseases that could mimic the clinical symptoms of CCDS. Symptoms ofCCDS include memory loss, which in domestic dogs may be manifested bydisorientation and/or confusion, decreased or altered interaction withfamily members and/or greeting behavior, changes in sleep-wake cycle,decreased activity level, and loss of house training or frequent,inappropriate elimination. A canine suffering from CCDS may exhibit oneor more of the following clinical or behavioral symptoms: decreasedappetite, decreased awareness of surroundings, decreased ability torecognize familiar places, people or other animals, decreased hearing,decreased ability to climb up and down stairs, decreased tolerance tobeing alone, development of compulsive behavior or repetitive behaviorsor habits, circling, tremors or shaking, disorientation, decreasedactivity level, abnormal sleep wake cycles, loss of house training,decreased or altered responsiveness to family members, and decreased oraltered greeting behavior. CCDS can dramatically affect the health andwell-being of an afflicted canine. Moreover, the companionship offeredby a pet with CCDS can become less rewarding as the severity of thedisease increases and its symptoms become more severe.

As used herein, the term “age-associated memory impairment” or “AAMI”refers to a condition that may be identified as GDS stage 2 on theglobal deterioration scale (GDS) (Reisberg, et al. (1982) Am. J.Psychiatry 139: 1136-1139) which differentiates the aging process andprogressive degenerative dementia in seven major stages. The first stageof the GDS is one in which individuals at any age have neithersubjective complaints of cognitive impairment nor objective evidence ofimpairment. These GDS stage 1 individuals are considered normal. Thesecond stage of the GDS applies to those generally elderly persons whocomplain of memory and cognitive functioning difficulties such as notrecalling names as well as they could five or ten years previously ornot recalling where they have placed things as well as they could fiveor ten years previously. These subjective complaints appear to be verycommon in otherwise normal elderly individuals. AAMI refers to personsin GDS stage 2, who may differ neurophysiologically from elderly personswho are normal and free of subjective complaints, i.e., GDS stage 1. Forexample, AAMI subjects have been found to have more electrophysiologicslowing on a computer analyzed EEG than GDS stage 1 elderly persons(Prichep, John, Ferris, Reisberg, et al. (1994) Neurobiol. Aging 15:85-90).

As used herein, the term “mild cognitive impairment” or “MC1” refers toa type of cognitive disorder characterized by a more pronounceddeterioration in cognitive functions than is typical for normalage-related decline. As a result, elderly or aged patients with MC1 havegreater than normal difficulty performing complex daily tasks andlearning, but without the inability to perform normal social, everyday,and/or professional functions typical of patients with Alzheimer'sdisease, or other similar neurodegenerative disorders eventuallyresulting in dementia. MC1 is characterized by subtle, clinicallymanifest deficits in cognition, memory, and functioning, amongst otherimpairments, which are not of sufficient magnitude to fulfill criteriafor diagnosis of Alzheimer's disease or other dementia. MC1 alsoencompasses injury-related MC1, defined herein as cognitive impairmentresulting from certain types of injury, such as nerve injury (i.e.,battlefield injuries, including post-concussion syndrome, and the like),neurotoxic treatment (i.e., adjuvant chemotherapy resulting in “chemobrain” and the like), and tissue damage resulting from physical injuryor other neurodegeneration, which is separate and distinct from mildcognitive impairment resulting from stroke, ischemia, hemorrhagicinsult, blunt force trauma, and the like.

As used herein, the term “traumatic brain injury” or “TBI” refers to abrain injury caused by a sudden trauma, such as a blow or jolt or apenetrating head injury, which disrupts the function or damages thebrain. Symptoms of TBI can range from mild, moderate to severe and cansignificantly affect many cognitive (deficits of language andcommunication, information processing, memory, and perceptual skills),physical (ambulation, balance, coordination, fine motor skills,strength, and endurance), and psychological skills.

“Neuronal death mediated ocular disease” intends an ocular disease inwhich death of the neuron is implicated in whole or in part. The diseasemay involve death of photoreceptors. The disease may involve retinalcell death. The disease may involve ocular nerve death by apoptosis.Particular neuronal death mediated ocular diseases include but are notlimited to macular degeneration, glaucoma, retinitis pigmentosa,congenital stationary night blindness (Oguchi disease), childhood onsetsevere retinal dystrophy, Leber congenital amaurosis, Bardet-Biedlesyndrome, Usher syndrome, blindness from an optic neuropathy, Leber'shereditary optic neuropathy, color blindness and Hansen-Larson-Bergsyndrome.

As used herein, the term “macular degeneration” includes all forms andclassifications of macular degeneration known in the art, including, butnot limited to diseases that are characterized by a progressive loss ofcentral vision associated with abnormalities of Bruch's membrane, thechoroid, the neural retina and/or the retinal pigment epithelium. Theterm thus encompasses disorders such as age-related macular degeneration(ARMD) as well as rarer, earlier-onset dystrophies that in some casescan be detected in the first decade of life. Other maculopathies includeNorth Carolina macular dystrophy, Sorsby's fundus dystrophy, Stargardt'sdisease, pattern dystrophy, Best disease, and Malattia Leventinese.

As used herein, the term “autism” refers to a brain development disorderthat impairs social interaction and communication and causes restrictedand repetitive behavior, typically appearing during infancy or earlychildhood. The cognitive and behavioral defects are thought to result inpart from altered neural connectivity. Autism encompasses relateddisorders sometimes referred to as “autism spectrum disorder,” as wellas Asperger syndrome and Rett syndrome.

As used herein, the term “nerve injury” or “nerve damage” refers tophysical damage to nerves, such as avulsion injury (i.e., where a nerveor nerves have been torn or ripped) or spinal cord injury (i.e., damageto white matter or myelinated fiber tracts that carry sensation andmotor signals to and from the brain). Spinal cord injury can occur frommany causes, including physical trauma (i.e., car accidents, sportsinjuries, and the like), tumors impinging on the spinal column,developmental disorders, such as spina bifida, and the like.

As used herein, the term “myasthenia gravis” or “MG” refers to anon-cognitive neuromuscular disorder caused by immune-mediated loss ofacetylcholine receptors at neuromuscular junctions of skeletal muscle.Clinically, MG typically appears first as occasional muscle weakness inapproximately two-thirds of patients, most commonly in the extraocularmuscles. These initial symptoms eventually worsen, producing droopingeyelids (ptosis) and/or double vision (diplopia), often causing thepatient to seek medical attention. Eventually, many patients developgeneral muscular weakness that may fluctuate weekly, daily, or even morefrequently. Generalized MG often affects muscles that control facialexpression, chewing, talking, swallowing, and breathing; before recentadvances in treatment, respiratory failure was the most common cause ofdeath.

As used herein, the term “Guillain-Barré syndrome” refers to anon-cognitive disorder in which the body's immune system attacks part ofthe peripheral nervous system. The first symptoms of this disorderinclude varying degrees of weakness or tingling sensations in the legs.In many instances the weakness and abnormal sensations spread to thearms and upper body. These symptoms can increase in intensity untilcertain muscles cannot be used at all and, when severe, the patient isalmost totally paralyzed. In these cases the disorder is lifethreatening—potentially interfering with breathing and, at times, withblood pressure or heart rate—and is considered a medical emergency. Mostpatients, however, recover from even the most severe cases ofGuillain-Barré syndrome, although some continue to have a certain degreeof weakness.

As used herein, the term “multiple sclerosis” or “MS” refers to anautoimmune condition in which the immune system attacks the centralnervous system (CNS), leading to demyelination of neurons. It may causenumerous symptoms, many of which are non-cognitive, and often progressesto physical disability. MS affects the areas of the brain and spinalcord known as the white matter. White matter cells carry signals betweenthe grey matter areas, where the processing is done, and the rest of thebody. More specifically, MS destroys oligodendrocytes which are thecells responsible for creating and maintaining a fatty layer, known asthe myelin sheath, which helps the neurons carry electrical signals. MSresults in a thinning or complete loss of myelin and, less frequently,the cutting (transection) of the neuron's extensions or axons. When themyelin is lost, the neurons can no longer effectively conduct theirelectrical signals. Almost any neurological symptom can accompany thedisease. MS takes several forms, with new symptoms occurring either indiscrete attacks (relapsing forms) or slowly accumulating over time(progressive forms). Most people are first diagnosed withrelapsing-remitting MS but develop secondary-progressive MS (SPMS) aftera number of years. Between attacks, symptoms may go away completely, butpermanent neurological problems often persist, especially as the diseaseadvances.

As used herein, the term “schizophrenia” refers to a chronic, mentaldisorder characterized by one or more positive symptoms (e.g., delusionsand hallucinations) and/or negative symptoms (e.g., blunted emotions andlack of interest) and/or disorganized symptoms (e.g., disorganizedthinking and speech or disorganized perception and behavior).Schizophrenia as used herein includes all forms and classifications ofschizophrenia known in the art, including, but not limited to catatonictype, hebephrenic type, disorganized type, paranoid type, residual typeor undifferentiated type schizophrenia and deficit syndrome and/or thosedescribed in American Psychiatric Association: Diagnostic andStatistical Manual of Mental Disorders, Fourth Edition, Washington D.C.,2000 or in International Statistical Classification of Diseases andRelated Health Problems, or otherwise known to those of skill in theart.

As used herein “geroprotective activity” or “geroprotector” means abiological activity that slows down ageing and/or prolongs life and/orincreases or improves the quality of life via a decrease in the amountand/or the level of intensity of pathologies or conditions that are notlife-threatening but are associated with the aging process and which aretypical for elderly people. Pathologies or conditions that are notlife-threatening but are associated with the aging process include suchpathologies or conditions as loss of sight (cataract), deterioration ofthe dermatohairy integument (alopecia), and an age-associated decreasein weight due to the death of muscular and/or fatty cells.

As used herein “allergic disease” refers to a disorder of the immunesystem which is characterized by excessive activation of mast cells andbasophils and production of IgE immunoglobulins, resulting in an extremeinflammatory response. It represents a form of hypersensitivity to anenvironmental substance known as allergen and is an acquired disease.Common allergic reactions include eczema, hives, hay fever, asthma, foodallergies, and reactions to the venom of stinging insects such as waspsand bees. Allergic reactions are accompanied by an excessive release ofhistamines, and can thus be treated with antihistaminic agents.

As used herein, by “combination therapy” is meant a therapy thatincludes two or more different compounds. Thus, in one aspect, acombination therapy comprising a compound detailed herein and anthercompound is provided. In some variations, the combination therapyoptionally includes one or more pharmaceutically acceptable carriers orexcipients, non-pharmaceutically active compounds, and/or inertsubstances. In various embodiments, treatment with a combination therapymay result in an additive or even synergistic (e.g., greater thanadditive) result compared to administration of a single compound of theinvention alone. In some embodiments, a lower amount of each compound isused as part of a combination therapy compared to the amount generallyused for individual therapy. Preferably, the same or greater therapeuticbenefit is achieved using a combination therapy than by using any of theindividual compounds alone. In some embodiments, the same or greatertherapeutic benefit is achieved using a smaller amount (e.g., a lowerdose or a less frequent dosing schedule) of a compound in a combinationtherapy than the amount generally used for individual compound ortherapy. Preferably, the use of a small amount of compound results in areduction in the number, severity, frequency, and/or duration of one ormore side-effects associated with the compound.

As used herein, the term “effective amount” intends such amount of acompound of the invention which in combination with its parameters ofefficacy and toxicity, as well as based on the knowledge of thepracticing specialist should be effective in a given therapeutic form.As is understood in the art, an effective amount may be in one or moredoses, i.e., a single dose or multiple doses may be required to achievethe desired treatment endpoint. An effective amount may be considered inthe context of administering one or more therapeutic agents, and asingle agent may be considered to be given in an effective amount if, inconjunction with one or more other agents, a desirable or beneficialresult may be or is achieved. Suitable doses of any of theco-administered compounds may optionally be lowered due to the combinedaction (e.g., additive or synergistic effects) of the compounds.

As used herein, “unit dosage form” refers to physically discrete units,suitable as unit dosages, each unit containing a predetermined quantityof active ingredient calculated to produce the desired therapeuticeffect in association with the required pharmaceutical carrier. Unitdosage forms may contain a single or a combination therapy.

As used herein, the term “controlled release” refers to adrug-containing formulation or fraction thereof in which release of thedrug is not immediate, i.e., with a “controlled release” formulation,administration does not result in immediate release of the drug into anabsorption pool. The term encompasses depot formulations designed togradually release the drug compound over an extended period of time.Controlled release formulations can include a wide variety of drugdelivery systems, generally involving mixing the drug compound withcarriers, polymers or other compounds having the desired releasecharacteristics (e.g., pH-dependent or non-pH-dependent solubility,different degrees of water solubility, and the like) and formulating themixture according to the desired route of delivery (e.g., coatedcapsules, implantable reservoirs, injectable solutions containingbiodegradable capsules, and the like).

As used herein, by “pharmaceutically acceptable” or “pharmacologicallyacceptable” is meant a material that is not biologically or otherwiseundesirable, e.g., the material may be incorporated into apharmaceutical composition administered to a patient without causing anysignificant undesirable biological effects or interacting in adeleterious manner with any of the other components of the compositionin which it is contained. Pharmaceutically acceptable carriers orexcipients have preferably met the required standards of toxicologicaland manufacturing testing and/or are included on the Inactive IngredientGuide prepared by the U.S. Food and Drug administration.

“Pharmaceutically acceptable salts” are those salts which retain atleast some of the biological activity of the free (non-salt) compoundand which can be administered as drugs or pharmaceuticals to anindividual. Such salts, for example, include: (1) acid addition salts,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or formedwith organic acids such as acetic acid, oxalic acid, propionic acid,succinic acid, maleic acid, tartaric acid and the like; (2) salts formedwhen an acidic proton present in the parent compound either is replacedby a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or analuminum ion; or coordinates with an organic base. Acceptable organicbases include ethanolamine, diethanolamine, triethanolamine and thelike. Acceptable inorganic bases include aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, andthe like. Pharmaceutically acceptable salts can be prepared in situ inthe manufacturing process, or by separately reacting a purified compoundof the invention in its free acid or base form with a suitable organicor inorganic base or acid, respectively, and isolating the salt thusformed during subsequent purification. It should be understood that areference to a pharmaceutically acceptable salt includes the solventaddition forms or crystal forms thereof, particularly solvates orpolymorphs. Solvates contain either stoichiometric or non-stoichiometricamounts of a solvent, and are often formed during the process ofcrystallization. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Polymorphs includethe different crystal packing arrangements of the same elementalcomposition of a compound. Polymorphs usually have different X-raydiffraction patterns, infrared spectra, melting points, density,hardness, crystal shape, optical and electrical properties, stability,and solubility. Various factors such as the recrystallization solvent,rate of crystallization, and storage temperature may cause a singlecrystal form to dominate.

The term “excipient” as used herein means an inert or inactive substancethat may be used in the production of a drug or pharmaceutical, such asa tablet containing a compound of the invention as an active ingredient.Various substances may be embraced by the term excipient, includingwithout limitation any substance used as a binder, disintegrant,coating, compression/encapsulation aid, cream or lotion, lubricant,solutions for parenteral administration, materials for chewable tablets,sweetener or flavoring, suspending/gelling agent, or wet granulationagent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.;coatings include, e.g., cellulose acetate phthalate, ethylcellulose,gellan gum, maltodextrin, enteric coatings, etc.;compression/encapsulation aids include, e.g., calcium carbonate,dextrose, fructose dc (dc “directly compressible”), honey dc, lactose(anhydrate or monohydrate; optionally in combination with aspartame,cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.;disintegrants include, e.g., croscarmellose sodium, gellan gum, sodiumstarch glycolate, etc.; creams or lotions include, e.g., maltodextrin,carrageenans, etc.; lubricants include, e.g., magnesium stearate,stearic acid, sodium stearyl fumarate, etc.; materials for chewabletablets include, e.g., dextrose, fructose dc, lactose (monohydrate,optionally in combination with aspartame or cellulose), etc.;suspending/gelling agents include, e.g., carrageenan, sodium starchglycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame,dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulationagents include, e.g., calcium carbonate, maltodextrin, microcrystallinecellulose, etc.

“Alkyl” refers to and includes saturated linear, branched, or cyclicunivalent hydrocarbon structures and combinations thereof. Particularalkyl groups are those having 1 to 20 carbon atoms (a “C₁-C₂₀ alkyl”).More particular alkyl groups are those having 1 to 8 carbon atoms (a“C₁-C₈ alkyl”). When an alkyl residue having a specific number ofcarbons is named, all geometric isomers having that number of carbonsare intended to be encompassed and described; thus, for example, “butyl”is meant to include n-butyl, sec-butyl, iso-butyl, tert-butyl andcyclobutyl; “propyl” includes n-propyl, iso-propyl and cyclopropyl. Thisterm is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl,cyclohexylmethyl, cyclopropyl and the like. Cycloalkyl is a subset ofalkyl and can consist of one ring, such as cyclohexyl, or multiplerings, such as adamantyl. A cycloalkyl comprising more than one ring maybe fused, spiro or bridged, or combinations thereof. In fused ringsystems, one or more of the rings can be aryl or heteroaryl. Acycloalkyl having more than one ring where at least one ring is aromaticmay be connected to the parent structure at either a non-aromatic ringposition or at an aromatic ring position. In one variation, a cycloalkylhaving more than one ring where at least one ring is aromatic isconnected to the parent structure at a non-aromatic ring position. Apreferred cycloalkyl is a saturated cyclic hydrocarbon having from 3 to13 annular carbon atoms. A more preferred cycloalkyl is a saturatedcyclic hydrocarbon having from 3 to 7 annular carbon atoms (a “C₃-C₇cycloalkyl”). Examples of cycloalkyl groups include adamantyl,decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl and thelike.

“Alkylene” refers to the same residues as alkyl, but having bivalency.Examples of alkylene include ethylene (—CH₂CH₂—) and propylene(—CH₂CH₂CH₂—).

“Alkenyl” refers to an unsaturated hydrocarbon group having at least onesite of olefinic unsaturation (i.e., having at least one moiety of theformula C═C) and preferably having from 2 to 10 carbon atoms and morepreferably 2 to 8 carbon atoms. Examples of alkenyl include but are notlimited to —CH₂—CH═CH—CH₃ and —CH₂—CH₂-cyclohexenyl, where the ethylgroup of the later example can be attached to the cyclohexenyl moiety atany available position on the ring.

“Alkynyl” refers to an unsaturated hydrocarbon group having at least onesite of acetylenic unsaturation (i.e., having at least one moiety of theformula C≡C) and preferably having from 2 to 10 carbon atoms and morepreferably 3 to 8 carbon atoms.

“Substituted alkyl” refers to an alkyl group having from 1 to 5substituents including, but not limited to, substituents such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkenyl” refers to alkenyl group having from 1 to 5substituents s including, but not limited to, substituents such asalkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 5substituents including, but not limited to, groups such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—,heteroaryl-C(O)—, substituted heteroaryl-C(O)—, heterocyclic-C(O)—, andsubstituted heterocyclic-C(O)—, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Acyloxy” refers to the groups H—C(O)O—, alkyl-C(O)O—, substitutedalkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—,alkynyl-C(O)O—, substituted alkynyl-C(O)O—, aryl-C(O)O—, substitutedaryl-C(O)O—, heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—,heterocyclic-C(O)O—, and substituted heterocyclic-C(O)O—, wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic are as defined herein.

“Heterocycle”, “heterocyclic”, or “heterocyclyl” refers to a saturatedor an unsaturated non-aromatic group having a single ring or multiplecondensed rings, and having from 1 to 10 annular carbon atoms and from 1to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen. Aheterocycle comprising more than one ring may be fused, spiro orbridged, or any combination thereof. In fused ring systems, one or moreof the rings can be aryl or heteroaryl. A heterocycle having more thanone ring where at least one ring is aromatic may be connected to theparent structure at either a non-aromatic ring position or at anaromatic ring position. In one variation, a heterocycle having more thanone ring where at least one ring is aromatic is connected to the parentstructure at a non-aromatic ring position.

“Substituted heterocyclic” or “substituted heterocyclyl” refers to aheterocycle group which is substituted with from 1 to 3 substituentsincluding, but not limited to, substituents such as alkoxy, substitutedalkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted orunsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy,substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol,thioalkyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo,carbonylalkylenealkoxy and the like. In one variation, a substitutedheterocycle is a heterocycle substituted with an additional ring,wherein the additional ring may be aromatic or non-aromatic.

“Aryl” or “Ar” refers to an unsaturated aromatic carbocyclic grouphaving a single ring (e.g., phenyl) or multiple condensed rings (e.g.,naphthyl or anthryl) which condensed rings may or may not be aromatic.In one variation, the aryl group contains from 6 to 14 annular carbonatoms. An aryl group having more than one ring where at least one ringis non-aromatic may be connected to the parent structure at either anaromatic ring position or at a non-aromatic ring position. In onevariation, an aryl group having more than one ring where at least onering is non-aromatic is connected to the parent structure at an aromaticring position.

“Heteroaryl” or “HetAr” refers to an unsaturated aromatic carbocyclicgroup having from 2 to 10 annular carbon atoms and at least one annularheteroatom, including but not limited to heteroatoms such as nitrogen,oxygen and sulfur. A heteroaryl group may have a single ring (e.g.,pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl,benzothienyl) which condensed rings may or may not be aromatic. Aheteroaryl group having more than one ring where at least one ring isnon-aromatic may be connected to the parent structure at either anaromatic ring position or at a non-aromatic ring position. In onevariation, a heteroaryl group having more than one ring where at leastone ring is non-aromatic is connected to the parent structure at anaromatic ring position.

“Substituted aryl” refers to an aryl group having 1 to 5 substituentsincluding, but not limited to, groups such as alkoxy, substitutedalkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted orunsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano,halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino,sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted heteroaryl” refers to a heteroaryl group having 1 to 5substituents including, but not limited to, groups such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy,cyano, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino,sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Aralkyl” refers to a residue in which an aryl moiety is attached to analkyl residue and wherein the aralkyl group may be attached to theparent structure at either the aryl or the alkyl residue. Preferably, anaralkyl is connected to the parent structure via the alkyl moiety. A“substituted aralkyl” refers to a residue in which an aryl moiety isattached to a substituted alkyl residue and wherein the aralkyl groupmay be attached to the parent structure at either the aryl or the alkylresidue.

“Alkoxy” refers to the group alkyl-O—, which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.Similarly, alkenyloxy refers to the group “alkenyl-O—” and alkynyloxyrefers to the group “alkynyl-O—”. “Substituted alkoxy” refers to thegroup substituted alkyl-O.

“Unsubstituted amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NR_(a)R_(b), where either (a)each R_(a) and R_(b) group is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, providedthat both R_(a) and R_(b) groups are not H; or (b) R_(a) and R_(b) arejoined together with the nitrogen atom to form a heterocyclic orsubstituted heterocyclic ring.

“Acylamino” refers to the group —C(O)NR_(a)R_(b) where R_(a) and R_(b)are independently selected from the group consisting of H, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic or R_(a) and R_(b) groups can bejoined together with the nitrogen atom to form a heterocyclic orsubstituted heterocyclic ring.

“Aminocarbonylalkoxy” refers to the group —NR_(a)C(O)OR_(b) where eachR_(a) and R_(b) group is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclyl.

“Aminoacyl” refers to the group —NR_(a)C(O)R_(b) where each R_(a) andR_(b) group is independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic or substituted heterocyclic. Preferably, R_(a)is H or alkyl.

“Aminosulfonyl” refers to the groups —NRSO₂-alkyl, —NRSO₂ substitutedalkyl, —NRSO₂-alkenyl, —NRSO₂-substituted alkenyl, —NRSO₂-alkynyl,—NRSO₂-substituted alkynyl, —NRSO₂-aryl, —NRSO₂-substituted aryl,—NRSO₂-heteroaryl, —NRSO₂-substituted heteroaryl, —NRSO₂-heterocyclic,and —NRSO₂-substituted heterocyclic, where R is H or alkyl and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Sulfonylamino” refers to the groups —SO₂NH₂, —SO₂NR-alkyl,—SO₂NR-substituted alkyl, —SO₂NR-alkenyl, —SO₂NR-substituted alkenyl,—SO₂NR-alkynyl, —SO₂NR-substituted alkynyl, —SO₂NR-aryl,—SO₂NR-substituted aryl, —SO₂NR-heteroaryl, —SO₂NR-substitutedheteroaryl, —SO₂NR-heterocyclic, and —SO₂NR-substituted heterocyclic,where R is H or alkyl, or —SO₂NR₂, where the two R groups are takentogether and with the nitrogen atom to which they are attached to form aheterocyclic or substituted heterocyclic ring.

“Sulfonyl” refers to the groups —SO₂-alkyl, —SO₂-substituted alkyl,—SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-alkynyl, —SO₂-substitutedalkynyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl,—SO₂-substituted heteroaryl, —SO₂-heterocyclic, and —SO₂-substitutedheterocyclic.

“Carbonylalkylenealkoxy” refers to the group —C(═O)—(CH₂)_(n)—OR where Ris a substituted or unsubstituted alkyl and n is an integer from 1 to100, more preferably n is an integer from 1 to 10 or 1 to 5.

“Halo” or “halogen” refers to elements of the Group 17 series havingatomic number 9 to 85. Preferred halo groups include the radicals offluorine, chlorine, bromine and iodine. Where a residue is substitutedwith more than one halogen, it may be referred to by using a prefixcorresponding to the number of halogen moieties attached, e.g.,dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may bebut are not necessarily the same halogen; thus 4-chloro-3-fluorophenylis within the scope of dihaloaryl. An alkyl group in which each H isreplaced with a halo group is referred to as a “perhaloalkyl.” Apreferred perhaloalkyl group is trifluoroalkyl (—CF₃). Similarly,“perhaloalkoxy” refers to an alkoxy group in which a halogen takes theplace of each H in the hydrocarbon making up the alkyl moiety of thealkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy(—OCF₃).

“Carbonyl” refers to the group C═O.

“Cyano” refers to the group —CN.

“Oxo” refers to the moiety ═O.

“Nitro” refers to the group —NO₂.

“Thioalkyl” refers to the groups —S-alkyl.

“Alkylsulfonylamino” refers to the groups —R¹SO₂NR_(a)R_(b) where R_(a)and R_(b) are independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, or the R_(a) andR_(b) groups can be joined together with the nitrogen atom to form aheterocyclic or substituted heterocyclic ring and R¹ is an alkyl group.

“Carbonylalkoxy” refers to as used herein refers to the groups—C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substitutedaryl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl,—C(O)O-substituted alkynyl, —C(O)O-heteroaryl, —C(O)O-substitutedheteroaryl, —C(O)O-heterocyclic or —C(O)O-substituted heterocyclic.

“Geminal” refers to the relationship between two moieties that areattached to the same atom. For example, in the residue —CH₂—CHR¹R², R¹and R² are geminal and R¹ may be referred to as a geminal R group to R²

“Vicinal” refers to the relationship between two moieties that areattached to adjacent atoms. For example, in the residue —CHR¹—CH₂R², R¹and R² are vicinal and R¹ may be referred to as a vicinal R group to R²

A composition of “substantially pure” compound means that thecomposition contains no more than 15% or preferably no more than 10% ormore preferably no more than 5% or even more preferably no more than 3%and most preferably no more than 1% impurity, which impurity may be thecompound in a different stereochemical form. For instance, a compositionof substantially pure S compound means that the composition contains nomore than 15% or no more than 10% or no more than 5% or no more than 3%or no more than 1% of the R form of the compound.

Compounds of the Invention

Compounds according to the invention are detailed herein, including inthe Brief Summary of the Invention and the appended claims. Theinvention includes the use of all of the compounds described herein,including any and all stereoisomers, salts and solvates of the compoundsdescribed as histamine receptor modulators.

The invention embraces compounds of the formula (I):

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R^(2a) and R^(2b)are taken together to form a carbonyl moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy, unsubstituted amino,substituted amino, cycloalkyl, acylamino or acyloxy or R^(3a) and R^(3b)are taken together to form a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

m and q are independently 0 or 1;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, thioalkyl, substituted or unsubstituted amino, acylamino,aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino oracyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, C₁-C₈ alkyl or is taken together with the carbon to whichit is attached and a geminal R₈ to form a cycloalkyl moiety or acarbonyl moiety;

each R^(10a) and R^(10b) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl or R^(1a) and R^(10b) aretaken together to form a carbonyl;

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl, substituted or a unsubstitutedheterocyclyl, unsubstituted amino, substituted amino, alkoxy, aminoacyl,acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino,

provided that the compound is other than a compound in Table 1,

or a salt or solvate thereof.

In one embodiment, compounds are of the formula (I) provided thecompound is other than a compound in Table 1 or Table 1a.

Compounds of the general formula (I) are described as new histaminereceptor modulators. Compounds of the invention may also find use intreating neurodegenerative diseases.

In another variation, the invention embraces compounds of the formula(I) or any variation herein, including any compound listed in Table 1 ora salt or solvate herein. In another variation, the invention embracescompounds of the formula (I) or any variation herein, including anycompound listed in Table 1a or a salt or solvate herein. In a particularvariation, the invention embraces methods of using compounds of theformula (I) or any variation herein, including any compound listed inTable 1 or a salt or solvate herein as detailed herein. In a particularvariation, the invention embraces methods of using compounds of theformula (I) or any variation herein, including any compound listed inTable 1a or a salt or solvate herein as detailed herein.

TABLE 1 No. Compound Name  1x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-4-hydroxy-3-(2- methylpropyl)-2-(2-propen-1-yl)-,1,1-dimethylethyl ester, (3S,4S)-  2x2H-Pyrido[3,4-b]indole-2-carboxamide,1,3,4,9-tetrahydro-N-1H-indazol-3-yl-9-[2-(4- morpholinyl)ethyl]-  4x1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-(methoxymethyl)-2-[(2E)-1-oxo-2,4-pentadienyl]-1-(2-propenyl)-, (1R)-  6x 9H-Pyrido[3,4-b]indole-9-aceticacid, 1,2,3,4-tetrahydro-2-[(phenylmethoxy)carbonyl]-, 1,1-dimethylethylester  7x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-(phenylmethyl)-2-[2-(2-pyridinyl)ethyl]-  9x1H-Pyrido[3,4-b]indol-1-one,6-butyl-2,9-bis[(4-fluorophenyl)methyl]-2,3,4,9-tetrahydro-  10x1H-Pyrido[3,4-b]indol-1-one,6-chloro-2,9-bis(4-chlorobenzoyl)-2,3,4,9-tetrahydro-  11x1H-Pyrido[3,4-b]indole,9-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-2,3,4,9-tetrahydro-2-[3-(3-pyridinyl)propyl]-  12x 1H-Pyrido[3,4-b]indole,2-[2,3:4,6-bis-O-(1-methylethylidene)-alpha-L-xylo-2-hexulofuranosonoyl]-9-(ethoxymethyl)-2,3,4,9-tetrahydro-1-methyl-,(1R)- 13x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-2-(4-hydroxybenzoyl)-9-[(4- hydroxyphenyl)methyl]- 15x 1H-Pyrido[3,4-b]indole-1-acetonitrile,2-(2-bromo-1-oxobutyl)-2,3,4,9-tetrahydro-9- (methoxymethyl)-,[S—(R*,R*)]-  16x 1H-Pyrido[3,4-b]indole,3-ethyl-2,3,4,9-tetrahydro-9-[2-(6-methyl-3-pyridinyl)ethyl]-  17x1H-Pyrido[3,4-b]indol-1-one,2-butyl-2,3,4,9-tetrahydro-6-(methylsulfonyl)-9- (phenylmethyl)-  18x1H-Pyrido[3,4-b]indole,6-chloro-9-(4-chlorobenzoyl)-2,3,4,9-tetrahydro-2- (trifluoroacetyl)- 21x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-2-(2-hydroxy-4-methylbenzoyl)-9-[(4-hydroxyphenyl)methyl]-  23x 4H-Pyrido[3,4-b]indol-4-one,1-ethyl-1,2,3,9-tetrahydro-9-(phenylmethyl)-  24x1H-Pyrido[3,4-b]indole-1-carbonitrile, 2-benzoyl-2,3,4,9-tetrahydro-1,9-bis(phenylmethyl)-  25x 1H-Pyrido[3,4-b]indol-1-one,6-bromo-9-[(4-bromophenyl)methyl]-2,3,4,9-tetrahydro-2- (phenylmethyl)- 26x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-2-[5-(methoxycarbonyl)-2- pyrimidinyl]-,1,1-dimethylethyl ester  27x 1H-Pyrido[3,4-b]indole,2-acetyl-2,3,4,9-tetrahydro-9-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-  30x Benz[cd]indol-2(1H)-one,2a,3,4,5-tetrahydro-2a-[4-[1,3,4,9-tetrahydro-9-(methoxymethyl)-2H-pyrido[3,4-b]indol-2-yl]butyl]-  32x1H-Pyrido[3,4-b]indol-1-one, 2-acetyl-2,3,4,9-tetrahydro-6-hydroxy-9-(2-piperidinoethyl)-  34x 1H-Pyrido[3,4-b]indol-1-one,9-[3-(cyclopentylamino)-2-hydroxypropyl]-2,3,4,9- tetrahydro-2-methyl- 35x 1H-Pyrido[3,4-b]indole-2,9-dicarboxylic acid,3,4-dihydro-1-[4-(phenylmethoxy)butyl]-, 9-(1,1-dimethylethyl) 2-methylester  42x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-3-(1-methylethyl)-4-oxo-2- (2-propen-1-yl)-,1,1-dimethylethyl ester, (3S)-  43x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-(2-methoxyethyl)-  45x9H-Pyrido[3,4-b]indole-9-acetic acid,1,2,3,4-tetrahydro-2-(4-hydroxybenzoyl)-, methyl ester  46x1H-Pyrido[3,4-b]indole-2,9-dicarboxylic acid,3,4-dihydro-1-(2-oxoethyl)-,9-(1,1- dimethylethyl) 2-(phenylmethyl)ester, (1S)-  47x 2H-Pyrido[3,4-b]indole-2-carboxylic acid,1,3,4,9-tetrahydro-9-(phenylmethyl)-, 1,1- dimethylethyl ester  48x4-Piperidinol,4-(4-chlorophenyl)-1-[3-[1,2,3,4-tetrahydro-2-[2-(2-pyridinyl)ethyl]-9H-pyrido[3,4-b]indol-9-yl]propyl]-  50x 1H-Pyrido[3,4-b]indol-1-one,6-butyl-2,3,4,9-tetrahydro-2,9-bis[(4- methylphenyl)methyl]-  51x1H-Pyrido[3,4-b]indol-1-one,6-chloro-2,9-bis[(4-chlorophenyl)methyl]-2,3,4,9- tetrahydro-  52x1H-Pyrido[3,4-b]indole, 2,3,4,9-tetrahydro-9-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-  53x 1H-Pyrido[3,4-b]indole,2-[2,3:4,6-bis-O-(1-methylethylidene)-alpha-L-xylo-2-hexulofuranosonoyl]-9-(ethoxymethyl)-2,3,4,9-tetrahydro-1-(2-phenylethyl)-,(1R)-  54x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-2-(2-hydroxybenzoyl)-9-[(4- hydroxyphenyl)methyl]- 56x 1H-Pyrido[3,4-b]indole-1-acetonitrile,2-[(2R)-2-bromo-1-oxobutyl]-2,3,4,9-tetrahydro-9- (methoxymethyl)-,(1S)-  57x 1H-Pyrido[3,4-b]indole,3-heptyl-2,3,4,9-tetrahydro-9-[2-(6-methyl-3-pyridinyl)ethyl]-  58x1H-Pyrido[3,4-b]indol-1-one,9-[(4-bromophenyl)methyl]-2,3,4,9-tetrahydro-6-(methylsulfonyl)-2-(phenylmethyl)-  59x 1H-Pyrido[3,4-b]indole,6-chloro-2,3,4,9-tetrahydro-9-(2-methoxybenzoyl)-2- (trifluoroacetyl)- 65x 1H-Pyrido[3,4-b]indole-1-carbonitrile,2-(4-chloro-1-oxobutyl)-2,3,4,9-tetrahydro-9- (phenylmethyl)-  66x1H-Pyrido[3,4-b]indol-1-one,6-bromo-2-[(4-fluorophenyl)methyl]-2,3,4,9-tetrahydro-9-[(4-methylphenyl)methyl]-  67x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-2-[5-(3-methoxy-3- oxopropyl)-2-pyrimidinyl]-,1,1-dimethylethyl ester  71x 9H-Pyrido[3,4-b]indole-9-carboxamide,N,N-diethyl-1,2,3,4-tetrahydro-2-[4-(1,2,4,5-tetrahydro-2-oxobenz[cd]indol-2a(3H)-yl)butyl]-  74x1H-Pyrido[3,4-b]indole-4-acetaldehyde,2,3,4,9-tetrahydro-2-[(4-methylphenyl)sulfonyl]- 9-(phenylmethyl)-,(4R)-  75x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-3-[(1S)-1-methylpropyl]-4- oxo-, 1,1-dimethylethylester, (3S)-  76x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-1-(4-hydroxybutyl)-2- methyl-, 1,1-dimethylethylester  81x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-(2-isopropoxyethyl)-3-methyl-  83x1H-Pyrido[3,4-b]indol-1-one,2,9-bis[(4-fluorophenyl)methyl]-2,3,4,9-tetrahydro-6- methoxy-  84x1H-Pyrido[3,4-b]indole, 9-benzyl-2,3,4,9-tetrahydro-1-methyl-  86x1H-Pyrido[3,4-b]indole,9-[(4-aminophenyl)methyl]-2,3,4,9-tetrahydro-2-(4- hydroxybenzoyl)-  88x2H-Pyrido[3,4-b]indole-2-butanoic acid, 1,3,4,9-tetrahydro-gamma-oxo-9-(phenylmethyl)-1-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-, phenylmethylester  91x 1H-Pyrido[3,4-b]indol-1-one,9-[(4-bromophenyl)methyl]-6-butyl-2,3,4,9-tetrahydro-2- (phenylmethyl)- 92x 1H-Pyrido[3,4-b]indol-1-one,2,9-dibenzoyl-6-chloro-2,3,4,9-tetrahydro-  93x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2-(1-oxo-2-propenyl)-  95x 1H-Pyrido[3,4-b]indole,2-[(6-amino-3-pyridinyl)carbonyl]-2,3,4,9-tetrahydro-9-[(4-hydroxyphenyl)methyl]-  98x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-3-(2-methylpropyl)-9-[2-(6-methyl-3-pyridinyl)ethyl]-  99x 1H-Pyrido[3,4-b]indol-1-one,2-benzoyl-2,3,4,9-tetrahydro-6-(methylsulfonyl)-9- (phenylmethyl)- 100x1H-Pyrido[3,4-b]indole,6-chloro-2,3,4,9-tetrahydro-9-(1-naphthalenylcarbonyl)-2-(trifluoroacetyl)- 101x 1H-Pyrido[3,4-b]indole,2-acetyl-9-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-2,3,4,9-tetrahydro- 103x 2H-Pyrido[3,4-b]indole-2-carboxylic acid,9-[(4-fluorophenyl)methyl]-1,3,4,9-tetrahydro-, phenylmethyl ester 105x2H-Pyrido[3,4-b]indole-2-ethanol,1,3,4,9-tetrahydro-1-methyl-beta-phenyl-9- (phenylmethyl)-, [S—(R*,S*)]-107x 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2,9-bis[(4-methylphenyl)methyl]-6-(trifluoromethoxy)- 109x 1H-Pyrido[3,4-b]indol-1-one,9-[3-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)-2-hydroxypropyl]-2,3,4,9-tetrahydro-2-methyl- 112x2H-Pyrido[3,4-b]indole-2-carboxylic acid,1,3,4,9-tetrahydro-9-[(methylamino)carbonyl]-, 1,1-dimethylethyl ester116x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-4-hydroxy-3-methyl-4- (phenylmethyl)-,1,1-dimethylethyl ester, (3S,4S)- 117x 1H-Pyrido[3,4-b]indole,2-(benzoyl-d5)-9-[(4-fluorophenyl)methyl]-2,3,4,9-tetrahydro- 121xBenzeneacetamide,alpha-cyclopentyl-N-(2-hydroxy-1-phenylethyl)-4-[(1,2,3,4-tetrahydro-2-methyl-1-oxo-9H-pyrido[3,4-b]indol-9-yl)methyl]- 122x1H-Pyrido[3,4-b]indole,9-(2-tert-butoxyethyl)-2,3,4,9-tetrahydro-3-methyl- 124x1H-Pyrido[3,4-b]indol-1-one,2,9-bis[(4-bromophenyl)methyl]-2,3,4,9-tetrahydro-6- methoxy- 126x1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-9-[2-hydroxy-3-[(4-methylphenyl)amino]propyl]-2-methyl- 127x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-[(4-hydroxyphenyl)methyl]-2-(4- methylbenzoyl)-129x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-3-(1-methylethyl)-4-oxo-2- (phenylsulfonyl)-,1,1-dimethylethyl ester, (3S)- 131x 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-6-methoxy-2,9-bis(phenylmethyl)- 132x1H-Pyrido[3,4-b]indol-1-one,6-butyl-2,3,4,9-tetrahydro-2-(2-propen-1-yl)-9-[[4-(trifluoromethyl)phenyl]methyl]- 133x2H-Pyrido[3,4-b]indole-2-carboxylic acid,9-benzoyl-1,3,4,9-tetrahydro-,ethyl ester 134x 1H-Pyrido[3,4-b]indole,2-benzoyl-2,3,4,9-tetrahydro-9-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- 136x 1H-Pyrido[3,4-b]indole,2-(4-chlorobenzoyl)-2,3,4,9-tetrahydro-9-[(4- hydroxyphenyl)methyl]-138x 1H-Pyrido[3,4-b]indole, 2,3,4,9-tetrahydro-9-(methoxymethyl)-2-(1-naphthalenylcarbonyl)-1-(2,4-pentadienyl)-, [S—(E)]- 139x1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-6-methoxy-9-[2-(6-methyl-3-pyridinyl)ethyl]-3-propyl- 140x 1H-Pyrido[3,4-b]indol-1-one,9-[(4-chlorophenyl)methyl]-2,3,4,9-tetrahydro-2-(1-methylethyl)-6-(methylsulfonyl)- 141x 1H-Pyrido[3,4-b]indole,6-chloro-2,3,4,9-tetrahydro-9-(phenylmethyl)-2-(trifluoroacetyl)- 142x9H-Pyrido[3,4-b]indole-9-carboxylic acid, 2-[[3-bromo-1-[(1,1-dimethylethoxy)carbonyl]-1H-indol-2-yl]methyl]-3-(butoxymethyl)-1,2,3,4-tetrahydro-4-oxo-, 1,1-dimethylethyl ester, (3S)- 143x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-6-methoxy-9-(2-naphthalenylcarbonyl)- 146x1H-Pyrido[3,4-b]indole-1-propanoic acid,2,3,4,9-tetrahydro-2-methyl-9-(phenylmethyl)-, methyl ester 147x1H-Pyrido[3,4-b]indole, 2,3,4,9-tetrahydro-9-(methoxymethyl)-1-methyl-148x 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2-propyl-6-(trifluoromethoxy)-9-[[4-(trifluoromethyl)phenyl]methyl]- 149x 5-Pyrimidinecarboxylic acid,2-[1,3,4,9-tetrahydro-9-(phenylmethyl)-2H-pyrido[3,4- b]indol-2-yl]-,methyl ester 150x 2H-Pyrido[3,4-b]indole-2-propionic acid,9-benzyl-1-(carboxymethyl)-1,3,4,9-tetrahydro-, diethyl ester 153x9H-Pyrido[3,4-b]indole-9-acetic acid,1,2,3,4-tetrahydro-2-[4-(1,2,4,5-tetrahydro-2-oxobenz[cd]indol-2a(3H)-yl)butyl]-, methyl ester 156x1H-Pyrido[3,4-b]indole,2-(4-butylbenzoyl)-9-(4-hydroxyphenyl)methyl-2,3,4,9- tetrahydro- 157x9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-4-hydroxy-3-[(1S)-1-methylpropyl]-4-(2-propen-1-yl)-, 1,1-dimethylethyl ester,(3S,4S)- 158x1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-9-[2-hydroxy-3-[[(tetrahydro-2-furanyl)methyl]amino]propyl]-2-methyl- 161x9H-Pyrido[3,4-b]indole-9-acetamide, 1,2,3,4-tetrahydro- 162xBenzeneacetic acid,alpha-cyclopentyl-4-[(1,2,3,4-tetrahydro-2-methyl-1-oxo-9H-pyrido[3,4-b]indol-9-yl)methyl]-, 1,1-dimethylethyl ester 163x2H-Pyrido[3,4-b]indole-2-carboxaldehyde,1-ethyl-1,3,4,9-tetrahydro-4-oxo-9- (phenylmethyl)- 165x1H-Pyrido[3,4-b]indol-1-one,9-[(4-bromophenyl)methyl]-2-butyl-2,3,4,9-tetrahydro-6- methoxy- 166x9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-1-(1-methylethyl)-, 1,1- dimethylethyl ester, (1S)-167x 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-9-[2-hydroxy-3-(4-morpholinyl)propyl]- 2-methyl- 168x1H-Pyrido[3,4-b]indole, 2,3,4,9-tetrahydro-2-(3-hydroxybenzoyl)-9-[(4-hydroxyphenyl)methyl]- 171x 1H-Pyrido[3,4-b]indole,2-acetyl-2,3,4,9-tetrahydro-1-methyl-9- [(pentafluorophenyl)methyl]-172x 1H-Pyrido[3,4-b]indol-1-ol,9-[2-(dimethylamino)ethyl]-2,3,4,9-tetrahydro-7-methoxy- 174x1H-Pyrido[3,4-b]indole,6-chloro-2,3,4,9-tetrahydro-9-(4-nitrobenzoyl)-2- (trifluoroacetyl)-175x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-[3-(1-piperidinyl)propyl]-2-[3-(4-pyridinyl)propyl]- 177x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-2-(4-hydroxybenzoyl)-9-[[4-(trifluoromethyl)phenyl]methyl]- 179x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-(methoxymethyl)-2-(1-oxo-2-butenyl)-1-(4-oxo-2-butenyl)-, (E,E)- 180x 9H-Pyrido[3,4-b]indole-9-propanamine,1,2,3,4-tetrahydro-N,N,1-trimethyl- 181x 1H-Pyrido[3,4-b]indol-1-one,6-bromo-2,9-bis[(4-bromophenyl)methyl]-2,3,4,9- tetrahydro- 182x2H-Pyrido[3,4-b]indole-2-propanoic acid,9-[(1,1-dimethylethoxy)carbonyl]-1,3,4,9- tetrahydro-7-hydroxy-,1,1-dimethylethyl ester 183x Phenol,4-[(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-9-yl)methyl]- 189x1H-Pyrido[3,4-b]indol-1-one,6-chloro-2,9-bis[(4-fluorophenyl)methyl]-2,3,4,9- tetrahydro- 191x1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-2-methyl-3-[[(4-methylphenyl)thio]methyl]-9-(phenylmethyl)-, (3S)- 197x1H-Pyrido[3,4-b]indol-1-one,9-benzyl-6-chloro-2-[3-(dimethylamino)propyl]-2,3,4,9- tetrahydro- 199x1H-Pyrido[3,4-b]indole, 9-benzyl-2,3,4,9-tetrahydro-2-methyl- 201x9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-,2,2,2-trichloroethyl ester 203x1H-Pyrido[3,4-b]indole,2-[2-(3,4-dimethoxyphenyl)ethyl]-2,3,4,9-tetrahydro-6-methoxy-9-(4-nitrobenzoyl)- 204x 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-3-methyl-2,9-bis(phenylmethyl)- 206x1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-6-methoxy-2-propyl-9-[[4-(trifluoromethyl)phenyl]methyl]- 208x 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-9-[2-hydroxy-3-(1-piperidinyl)propyl]-2- methyl- 209x1H-Pyrido[3,4-b]indole,2-(3,5-dichloro-2-hydroxybenzoyl)-2,3,4,9-tetrahydro-9-[(4-hydroxyphenyl)methyl]- 212x 1H-Pyrido[3,4-b]indol-1-one,9-(2-aminoethyl)-2,3,4,9-tetrahydro-6-methoxy-2-methyl- 213x1H-Pyrido[3,4-b]indole,3-butyl-2,3,4,9-tetrahydro-1-methyl-9-[2-(6-methyl-3- pyridinyl)ethyl]-214x 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-6-(methylsulfonyl)-2,9-bis[[4-(trifluoromethyl)phenyl]methyl]- 215x 1H-Pyrido[3,4-b]indole,6-chloro-2,3,4,9-tetrahydro-2-(trifluoroacetyl)-9-[2-(trifluoromethyl)benzoyl]- 218x 1H-Pyrido[3,4-b]indole,2-(5-chloro-2-hydroxybenzoyl)-2,3,4,9-tetrahydro-9-[(4-hydroxyphenyl)methyl]- 220x 1H-Pyrido[3,4-b]indole,2-acetyl-2,3,4,9-tetrahydro-9-(phenylmethyl)- 221x1H-Pyrido[3,4-b]indole-1-carbonitrile,2-benzoyl-2,3,4,9-tetrahydro-9-(phenylmethyl)- 222x1H-Pyrido[3,4-b]indol-1-one, 6-bromo-2,3,4,9-tetrahydro-2,9-bis[(4-methylphenyl)methyl]- 224x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-[3-(1-piperidinyl)propyl]-2-[2-(2-pyridinyl)ethyl]- 227x 2H-Pyrido[3,4-b]indole-2-carboxylic acid,1,3,4,9-tetrahydro-9-(methoxymethyl)-, 1,1- dimethylethyl ester 229x9H-Pyrido[3,4-b]indole-9-ethanamine, 1,2,3,4-tetrahydro-N,N,3-trimethyl-230x 1H-Pyrido[3,4-b]indol-1-one,9-[(4-bromophenyl)methyl]-6-chloro-2,3,4,9-tetrahydro-2- (phenylmethyl)-231x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-2-[5-[(1E)-3-methoxy-3-oxo-1-propenyl]-2-pyrimidinyl]-, 1,1-dimethylethyl ester 232x1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-9-[2-hydroxy-3-[4-(2-hydroxyethyl)-1-piperazinyl]propyl]-2-methyl- 235x 9H-Pyrido[3,4-b]indole-9-acetamide,1,2,3,4-tetrahydro-N,N-dimethyl- 238x 1H-Pyrido[3,4-b]indol-1-one,9-benzyl-2,3,4,9-tetrahydro-6-methoxy-2-[3-(1- pyrrolidinyl)propyl]-239x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-4-hydroxy-3-methyl-2-(2- propen-1-yl)-,1,1-dimethylethyl ester, (3S,4S)- 240x 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-9-[2-hydroxy-3-[(2-hydroxyethyl)amino]propyl]-2-methyl- 241x1H-Pyrido[3,4-b]indole-2,9-dicarboxylic acid,3,4-dihydro-4-(2-oxo-2-phenylethyl)-, bis(1,1-dimethylethyl) ester 242x9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-2-[[(2R)-4-methyl-2-[(4R)-2-oxo-4-(phenylmethyl)-3-oxazolidinyl]pentyl]sulfonyl]-,2,2,2-trichloroethylester 243x 9H-Pyrido[3,4-b]indole-9-carboxamide,1,2,3,4-tetrahydro-N-methyl- 244x 9H-Pyrido[3,4-b]indole-9-carboxylicacid, 2-acetyl-1,2,3,4-tetrahydro-6-methoxy-1- methylene-, ethyl ester247x 1H-Pyrido[3,4-b]indol-1-one,2,9-bis[(4-bromophenyl)methyl]-6-butyl-2,3,4,9- tetrahydro- 248x1H-Pyrido[3,4-b]indol-1-one, 2,9-dibenzoyl-6-bromo-2,3,4,9-tetrahydro-249x 1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-9-[2-hydroxy-3-[(4-methoxyphenyl)amino]propyl]-2-methyl- 250x Benzeneacetamide,alpha-cyclopentyl-N-[(1R)-2-hydroxy-1-phenylethyl]-4-[(1,2,3,4-tetrahydro-2-methyl-1-oxo-9H-pyrido[3,4-b]indol-9-yl)methyl]- 254x1H-Pyrido[3,4-b]indole,3-butyl-2,3,4,9-tetrahydro-9-[2-(2-pyridinyl)ethyl]- 255x1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-6-(methylsulfonyl)-2-propyl-9-[[4-(trifluoromethyl)phenyl]methyl]- 256x 1H-Pyrido[3,4-b]indole,6-chloro-9-(2-chlorobenzoyl)-2,3,4,9-tetrahydro-2- (trifluoroacetyl)-259x 1H-Pyrido[3,4-b]indole,2-(3,5-dichloro-4-hydroxybenzoyl)-9-[(4-fluorophenyl)methyl]-2,3,4,9-tetrahydro- 262x 1H-Pyrido[3,4-b]indole-1-carbonitrile,2-benzoyl-2,3,4,9-tetrahydro-1-methyl-9- (phenylmethyl)- 263x1H-Pyrido[3,4-b]indol-1-one,6-bromo-2,9-bis[(2-fluorophenyl)methyl]-2,3,4,9- tetrahydro- 265x1H-Pyrido[3,4-b]indole,2-(cyclohexylcarbonyl)-2,3,4,9-tetrahydro-9-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]- 268x2H-Pyrido[3,4-b]indole-2-carboxylic acid,9-(2-amino-2-oxoethyl)-1,3,4,9-tetrahydro-, 1,1-dimethylethyl ester 270x1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2-phenyl-9-(phenylmethyl)- 271x1H-Pyrido[3,4-b]indol-1-one,6-chloro-2,3,4,9-tetrahydro-9-[(4-nitrophenyl)methyl]-2- (phenylmethyl)-272x 1H-Pyrido[3,4-b]indol-1-one,9-[3-(azepan-1-yl)-2-hydroxypropyl]-2,3,4,9-tetrahydro-2- methyl- 276x2H-Pyrido[3,4-b]indole-2-carboxylic acid,9-[2-(acetyloxy)ethyl]-1,3,4,9-tetrahydro-, 1,1- dimethylethyl ester279x 1H-Pyrido[3,4-b]indole,2-acetyl-9-[3-(dimethylamino)propyl]-2,3,4,9-tetrahydro-6- methoxy- 280x1H-Pyrido[3,4-b]indol-1-one,9-[3-[(4-chlorophenyl)amino]-2-hydroxypropyl]-2,3,4,9-tetrahydro-2-methyl- 282x Propanedioic acid,[2-[9-[(1,1-dimethylethoxy)carbonyl]-2,3,4,9-tetrahydro-2-(2-iodo-2-butenyl)-1H-pyrido[3,4-b]indol-1-yl]ethylidene]-, dimethylester 283x2H-Pyrido[3,4-b]indole-2-carboxylic acid, 9-[[(2S)-1-[[4-(1,1-dimethylpropyl)phenyl]sulfonyl]-2-pyrrolidinyl]carbonyl]-1,3,4,9-tetrahydro-1-(2-propenyl)-, 2,2,2-trichloroethyl ester, (1R)- 284x1H-Pyrido[3,4-b]indole-2,9-dicarboxylic acid,3,4-dihydro-1-(2-oxoethyl)-,9-( 1,1- dimethylethyl) 2-(phenylmethyl)ester, (1R)- 285x 9H-Pyrido[3,4-b]indole-9-acetic acid,1,2,3,4-tetrahydro-,1,1-dimethylethyl ester 286x 1H-Pyrido[3,4-b]indole,9-[(4-fluorophenyl)methyl]-2,3,4,9-tetrahydro-2-[2-(2- pyridinyl)ethyl]-288x 1H-Pyrido[3,4-b]indol-1-one,6-butyl-2,3,4,9-tetrahydro-2,9-bis[(4-nitrophenyl)methyl]- 289x2H-Pyrido[3,4-b]indole-2-carboxylic acid,6-bromo-9-[(4-chlorophenyl)methyl]-1,3,4,9- tetrahydro-1,1-dimethyl-,ethyl ester 290x 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-6-methoxy-9-(phenylmethyl)-2-[3-(1-piperidinyl)propyl]- 291x 1H-Pyrido[3,4-b]indole,2-[2,3:4,6-bis-O-(1-methylethylidene)-alpha-L-xylo-2-hexulofuranosonoyl]-9-(ethoxymethyl)-2,3,4,9-tetrahydro-1-(2-propenyl)-,(1R)- 292x 1H-Pyrido[3,4-b]indole,2-benzoyl-2,3,4,9-tetrahydro-9-[(4-hydroxyphenyl)methyl]- 295x1H-Pyrido[3,4-b]indole,3-heptyl-2,3,4,9-tetrahydro-6-methoxy-9-[2-(6-methyl-3-pyridinyl)ethyl]- 296x 1H-Pyrido[3,4-b]indol-1-one,9-[(4-bromophenyl)methyl]-2,3,4,9-tetrahydro-6-(methylsulfonyl)-2-propyl- 297x 1H-Pyrido[3,4-b]indole,9-(2-bromobenzoyl)-6-chloro-2,3,4,9-tetrahydro-2- (trifluoroacetyl)-298x 1H-Pyrido[3,4-b]indole,2-benzoyl-2,3,4,9-tetrahydro-9-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]- 303x 1H-Pyrido[3,4-b]indole-1-carbonitrile,2-benzoyl-1,9-bis[(4-bromophenyl)methyl]- 2,3,4,9-tetrahydro- 304x1H-Pyrido[3,4-b]indol-1-one,6-bromo-9-[(4-fluorophenyl)methyl]-2,3,4,9-tetrahydro-2- (phenylmethyl)-305x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-2-[5-(hydroxymethyl)-2- pyrimidinyl]-,1,1-dimethylethyl ester 306x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-2-(phenylacetyl)- 309x9H-Pyrido[3,4-b]indole-9-acetamide,1,2,3,4-tetrahydro-2-[4-(1,2,4,5-tetrahydro-2-oxobenz[cd]indol-2a(3H)-yl)butyl]- 313x9H-Pyrido[3,4-b]indole-9-carboxylic acid,4-ethyl-1,2,3,4-tetrahydro-4-hydroxy-3-(1-methylethyl)-2-(phenylsulfonyl)-, 1,1-dimethylethyl ester,(3S,4S)- 314x1H-Pyrido[3,4-b]indole-2,9-dicarboxylic acid,3,4-dihydro-1-(4-oxobutyl)-,9-(1,1- dimethylethyl) 2-methyl ester 320x1H-Pyrido[3,4-b]indole,9-[3-(dimethylamino)propyl]-2,3,4,9-tetrahydro-6-methoxy-2- methyl- 321x9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-3-(2-methylpropyl)-4-oxo- 2-(2-propen-1-yl)-,1,1-dimethylethyl ester, (3S)- 322x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-[2-(4-morpholinyl)ethyl]- 323x 2,6-Octadien-1-ol,8-[2,3,4,9-tetrahydro-9-(methoxymethyl)-1H-pyrido[3,4-b]indol-1-yl]-,acetate (ester), (2E,6E)- 324x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-2-(4-hydroxybenzoyl)-9-(phenylmethyl)- 326x2H-Pyrido[3,4-b]indole-2-carboxamide,1,3,4,9-tetrahydro-N-(3-methylphenyl)-9- (phenylmethyl)- 329x1H-Pyrido[3,4-b]indol-1-one,6-butyl-2,3,4,9-tetrahydro-2,9-bis(phenylmethyl)- 330x1H-Pyrido[3,4-b]indol-1-one,6-chloro-2,3,4,9-tetrahydro-2,9-bis(4-methoxybenzoyl)- 333x1H-Pyrido[3,4-b]indole,2-(1H-benzimidazol-5-ylcarbonyl)-2,3,4,9-tetrahydro-9-[(4-hydroxyphenyl)methyl]- 336x 1H-Pyrido[3,4-b]indole,3-hexyl-2,3,4,9-tetrahydro-9-[2-(6-methyl-3-pyridinyl)ethyl]- 337x1H-Pyrido[3,4-b]indol-1-one,9-[(4-chlorophenyl)methyl]-2,3,4,9-tetrahydro-6-(methylsulfonyl)-2-(phenylmethyl)- 338x 1H-Pyrido[3,4-b]indole,6-chloro-2,3,4,9-tetrahydro-9-(3-methoxybenzoyl)-2- (trifluoroacetyl)-339x 9H-Pyrido[3,4-b]indole-9-propanamine,1,2,3,4-tetrahydro-N,N-dimethyl-2-[3-(4- pyridinyl)propyl]- 341x2H-Pyrido[3,4-b]indole-2-carboxylic acid, 1,3,4,9-tetrahydro-9-[[4-(trifluoromethyl)phenyl]methyl]-, phenylmethyl ester 343x1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-1-methyl-9-(phenylmethyl)-,(S)- 345x1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-2,9-bis(phenylmethyl)-6-(trifluoromethoxy)- 346x 5-Pyrimidinecarboxylic acid,2-[1,3,4,9-tetrahydro-9-[2-(1-pyrrolidinyl)ethyl]-2H-pyrido[3,4-b]indol-2-yl]-, methyl ester 347x 1H-Pyrido[3,4-b]indole,9-[2-[4-(3-chlorophenyl)-1-piperazinyl]ethyl]-2,3,4,9-tetrahydro- 350x9H-Pyrido[3,4-b]indole-9-carboxamide,1,2,3,4-tetrahydro-2-[4-(1,2,4,5-tetrahydro-2-oxobenz[cd]indol-2a(3H)-yl)butyl]- 353x9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-6-methoxy-2,4,4-trimethyl- 1-oxo-, 1,1-dimethylethylester 354x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-3-(2-methylpropyl)-4-oxo-, 1,1-dimethylethyl ester,(3S)- 355x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-2-[(4- methylphenyl)sulfonyl]-1-(4-oxobutyl)-,1,1-dimethylethyl ester 360x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-(2-isobutoxyethyl)-3-methyl- 361x9H-Pyrido[3,4-b]indole-9-propanamine,N,N-diethyl-1,2,3,4-tetrahydro-6-methoxy- 362x1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-6-methoxy-2,9-bis[[4-(trifluoromethyl)phenyl]methyl]- 364x 1H-Pyrido[3,4-b]indole,9-([1,1′-biphenyl]-4-ylcarbonyl)-2,3,4,9-tetrahydro-6-methoxy-2- methyl-365x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-2-(4-hydroxybenzoyl)-9-[[4-(methylsulfonyl)phenyl]methyl]- 366x9H-Pyrido[3,4-b]indole-9-carboxamide,1,2,3,4-tetrahydro-N,N-dimethyl-2-[4-[(2aS)-1,2,4,5-tetrahydro-4-oxobenz[cd]indol-2a(3H)-yl]butyl]- 367x9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-3-methyl-4-oxo-2- (phenylsulfonyl)-,1,1-dimethylethyl ester, (3S)- 369x 1H-Pyrido[3,4-b]indole,9,9′-methylenebis[2,3,4,9-tetrahydro-2-methyl- 370x1H-Pyrido[3,4-b]indol-1-one,6-butyl-9-[(3-fluorophenyl)methyl]-2,3,4,9-tetrahydro-2-(2-propen-1-yl)- 371x 1H-Pyrido[3,4-b]indole,9-benzoyl-6-chloro-2,3,4,9-tetrahydro-2-(trifluoroacetyl)- 372x1H-Pyrido[3,4-b]indole-1-acetic acid,2,3,4,9-tetrahydro-9-(phenylmethyl)-, ethyl ester 373x9H-Pyrido[3,4-b]indole-9-carboxamide, 1,2,3,4-tetrahydro-N,N-dimethyl-374x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-[(4-hydroxyphenyl)methyl]-2-[4-(methylamino)benzoyl]- 376x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-(methoxymethyl)-1-(2,4-pentadienyl)-, [S—(E)]- 377x1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-6-methyl-3-(3-methylbutyl)-9-[2-(6-methyl-3-pyridinyl)ethyl]- 378x 1H-Pyrido[3,4-b]indol-1-one,9-[(4-chlorophenyl)methyl]-2,3,4,9-tetrahydro-6-(methylsulfonyl)-2-propyl- 379x 1H-Pyrido[3,4-b]indole,6-chloro-2,3,4,9-tetrahydro-9-(2-naphthalenylcarbonyl)-2-(trifluoroacetyl)- 380x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,2-[(2-bromophenyl)methyl]-1,2,3,4-tetrahydro- 3-methyl-4-oxo-,1,1-dimethylethyl ester, (3S)- 386x 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-6-(trifluoromethoxy)-2,9-bis[[4-(trifluoromethyl)phenyl]methyl]- 387x 5-Pyrimidinecarboxylic acid,2-[1,3,4,9-tetrahydro-9-[2-(4-morpholinyl)ethyl]-2H-pyrido[3,4-b]indol-2-yl]- 388x 1H-Pyrido[3,4-b]indol-1-one,9-[3-(benztriazol-1(1H)-yl)-2-hydroxypropyl]-2,3,4,9-tetrahydro-2-methyl- 391x 9H-Pyrido[3,4-b]indole-9-carboxamide,1,2,3,4-tetrahydro-N-methyl-2-[4-(1,2,4,5-tetrahydro-2-oxobenz[cd]indol-2a(3H)-yl)butyl]- 394x1H-Pyrido[3,4-b]indol-1-one,9-[3-(3,5-dimethyl-1H-pyrazol-1-yl)-2-hydroxypropyl]-2,3,4,9-tetrahydro-2-methyl- 395x 9H-Pyrido[3,4-b]indole-9-carboxylicacid, 1,2,3,4-tetrahydro-4-hydroxy-3-methyl-4-(2- propen-1-yl)-,1,1-dimethylethyl ester, (3S,4S)- 396x 1H-Pyrido[3,4-b]indole,2-(4-bromobenzoyl)-9-[(4-cyanophenyl)methyl]-2,3,4,9- tetrahydro- 399x9H-Pyrido[3,4-b]indole-9-carboxylic acid, 1,2,3,4-tetrahydro-, methylester 400x Benzeneacetamide,alpha-cyclopentyl-N-(phenylmethyl)-4-[(1,2,3,4-tetrahydro-2-methyl-1-oxo-9H-pyrido[3,4-b]indol-9-yl)methyl]- 403x1H-Pyrido[3,4-b]indol-1-one,9-[(4-bromophenyl)methyl]-2,3,4,9-tetrahydro-6-methoxy-2-(phenylmethyl)- 405x 1H-Pyrido[3,4-b]indol-1-one,9-[3-(di-2-propenylamino)-2-hydroxypropyl]-2,3,4,9- tetrahydro-2-methyl-406x 1H-Pyrido[3,4-b]indole,2-(2,4-dichlorobenzoyl)-2,3,4,9-tetrahydro-9-[(4- hydroxyphenyl)methyl]-410x 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2-methyl-9-(phenylmethyl)- 411x1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-6-(methylthio)-2,9-bis(phenylmethyl)- 412x1H-Pyrido[3,4-b]indole-2,9-dicarboxylic acid, 3,4-dihydro-,2-ethyl9-phenyl ester 413x 1H-Pyrido[3,4-b]indole,9-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-2,3,4,9-tetrahydro-2-[2-(2-pyridinyl)ethyl]- 415x 1H-Pyrido[3,4-b]indole,2-(3,5-dichloro-4-hydroxybenzoyl)-2,3,4,9-tetrahydro-9-[(4-hydroxyphenyl)methyl]- 417x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-(methoxymethyl)-2-(1-oxo-2,4-pentadienyl)-1-(2-propenyl)-, [S—(E)]- 418x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-6-methyl-9-[2-(6-methyl-3-pyridinyl)ethyl]-3- propyl-419x 1H-Pyrido[3,4-b]indol-1-one,2-butyl-9-[(4-chlorophenyl)methyl]-2,3,4,9-tetrahydro-6-(methylsulfonyl)- 420x 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-9-[2-hydroxy-3-(10H-phenothiazin-10-yl)propyl]-2-methyl- 421x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,2-[(3-bromo-2-thienyl)methyl]-1,2,3,4-tetrahydro-3-(1-methylethyl)-4-oxo-, 1,1-dimethylethyl ester,(3S)- 422x1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-6-methoxy-9-(2-naphthalenylmethyl)- 425x1H-Pyrido[3,4-b]indole-1-propanal,2,3,4,9-tetrahydro-2-methyl-9-(phenylmethyl)- 426x1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-(methoxymethyl)-1-(2-methylpropyl)- 427x1H-Pyrido[3,4-b]indol-1-one,6-chloro-2,3,4,9-tetrahydro-9-[(4-methylphenyl)methyl]-2-(phenylmethyl)- 428x 5-Pyrimidinecarboxylic acid,2-[1,3,4,9-tetrahydro-9-(phenylmethyl)-2H-pyrido[3,4- b]indol-2-yl]-429x Benzoic acid, 3,4,5-trimethoxy-,3-(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-9-yl)propyl ester 432x2H-Pyrido[3,4-b]indole-2-carboxylic acid,1,3,4,9-tetrahydro-9-[2-(methylamino)-2- oxoethyl]-, 1,1-dimethylethylester 435x 1H-Pyrido[3,4-b]indol-1-one,9-benzyl-2-[2-(dimethylamino)ethyl]-2,3,4,9-tetrahydro-6- methoxy- 436x9H-Pyrido[3,4-b]indole-9-carboxylic acid,4-(3-buten-1-yl)-1,2,3,4-tetrahydro-4-hydroxy- 3-methyl-,1,1-dimethylethyl ester, (3S,4S)- 437x 1H-Pyrido[3,4-b]indole,9-(3-aminopropyl)-2,3,4,9-tetrahydro- 438x1H-Pyrido[3,4-b]indole-2,9-dicarboxylic acid,3,4-dihydro-4-methylene-1-oxo-, bis(1,1- dimethylethyl) ester 439x9H-Pyrido[3,4-b]indole-9-carboxylic acid, 2-[[2-carboxy-2-[1-[(phenylmethoxy)carbonyl]-4-piperidinyl]ethyl]sulfonyl]-1,2,3,4-tetrahydro-,9-(2,2,2- trichloroethyl) ester 441x Benzeneacetic acid,alpha-cyclopentyl-4-[(1,2,3,4-tetrahydro-2-methyl-1-oxo-9H-pyrido[3,4-b]indol-9-yl)methyl]- 442x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-2,9-bis(phenylmethyl)- 444x1H-Pyrido[3,4-b]indol-1-one, 2-butyl-2,3,4,9-tetrahydro-6-methoxy-9-[[4-(trifluoromethyl)phenyl]methyl]- 445x9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-1-(phenylmethyl)-, 1,1- dimethylethyl ester, (1S)-446x 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-9-[2-hydroxy-3-(2-methyl-1H-benzimidazol-1-yl)propyl]-2-methyl- 447x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-[(4-hydroxyphenyl)methyl]-2-(4- methoxybenzoyl)-449x 1H-Pyrido[3,4-b]indole-2,9-dicarboxylic acid,3,4-dihydro-4-oxo-,bis(1,1-dimethylethyl)ester 451x1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-[2-(6-methyl-3-pyridinyl)ethyl]-3-methyl- 452x1H-Pyrido[3,4-b]indol-1-one,2,9-bis[(4-bromophenyl)methyl]-2,3,4,9-tetrahydro-6- (methylsulfonyl)-453x 1H-Pyrido[3,4-b]indole,6-chloro-9-(3-cyanobenzoyl)-2,3,4,9-tetrahydro-2- (trifluoroacetyl)-456x Benzoic acid,4-[[1,2,3,4-tetrahydro-2-(4-hydroxybenzoyl)-9H-pyrido[3,4-b]indol-9-yl]methyl]-, methyl ester 458x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-(phenylmethyl)- 459x9H-Pyrido[3,4-b]indole-9-propanamine,1-ethyl-1,2,3,4-tetrahydro-N,N-dimethyl- 460x1H-Pyrido[3,4-b]indol-1-one, 6-bromo-2,3,4,9-tetrahydro-2,9-bis[[4-(trifluoromethyl)phenyl]methyl]- 462x 1H-Pyrido[3,4-b]indole,2-acetyl-2,3,4,9-tetrahydro-9-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]- 468x 1H-Pyrido[3,4-b]indol-1-one,6-chloro-2,3,4,9-tetrahydro-2,9-bis(phenylmethyl)- 470x1H-Pyrido[3,4-b]indol-1-one, 2-ethyl-2,3,4,9-tetrahydro-3-[[(4-methylphenyl)thio]methyl]-9-(phenylmethyl)-, (3S)- 473x9H-Pyrido[3,4-b]indole-9-acetamide,1,2,3,4-tetrahydro-N-methyl-2-[4-(1,2,4,5-tetrahydro-2-oxobenz[cd]indol-2a(3H)-yl)butyl]- 478x9H-Pyrido[3,4-b]indole-9-ethanol,1,2,3,4-tetrahydro-,3,4,5-trimethoxybenzoate 480x9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-2-[[[tetrahydro-4-(methoxycarbonyl)-2H-pyran-4-yl]methyl]sulfonyl]-,2,2,2-trichloroethylester 481x 9H-Pyrido[3,4-b]indole-9-carboxamide, 1,2,3,4-tetrahydro-483x 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2,9-bis(phenylmethyl)- 485x1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-6-methoxy-2-(phenylmethyl)-9-[[4-(trifluoromethyl)phenyl]methyl]- 486x 1H-Pyrido[3,4-b]indol-1-one,6-bromo-2,9-bis(3-chlorobenzoyl)-2,3,4,9-tetrahydro- 487x1H-Pyrido[3,4-b]indol-1-one,9-[3-(4,5-diphenyl-1H-imidazol-1-yl)-2-hydroxypropyl]-2,3,4,9-tetrahydro-2-methyl- 488x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-2-(4-hydroxy-3,5-dimethylbenzoyl)-9-[(4-hydroxyphenyl)methyl]- 492x 1H-Pyrido[3,4-b]indole,3-butyl-2,3,4,9-tetrahydro-9-[2-(6-methyl-3-pyridinyl)ethyl]- 493x1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-6-(methylsulfonyl)-2,9-bis(phenylmethyl)- 494x 1H-Pyrido[3,4-b]indole,6-chloro-2,3,4,9-tetrahydro-2-(trifluoroacetyl)-9-[2-(trifluoromethoxy)benzoyl]- 495x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-[2-[4-(2-methoxyphenyl)-1- piperazinyl]ethyl]- 497x1H-Pyrido[3,4-b]indole,9-[(4-fluorophenyl)methyl]-2,3,4,9-tetrahydro-2-(4- hydroxybenzoyl)-498x 1H-Pyrido[3,4-b]indole,2-(4-cyanobenzoyl)-9-[(3-cyanophenyl)methyl]-2,3,4,9- tetrahydro- 500x1H-Pyrido[3,4-b]indole-1-carbonitrile,2-[2-(chloromethyl)benzoyl]-2,3,4,9-tetrahydro-9- (phenylmethyl)- 501x1H-Pyrido[3,4-b]indol-1-one,6-bromo-2,9-bis[(3-fluorophenyl)methyl]-2,3,4,9- tetrahydro- 503xBenzoic acid,4-[(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-9-yl)methyl]-,methyl ester506x 2H-Pyrido[3,4-b]indole-2-carboxylic acid,9-[(dimethylamino)carbonyl]-1,3,4,9- tetrahydro-, 1,1-dimethylethylester 508x 2-Butenoic acid,3-methoxy-4-[2,3,4,9-tetrahydro-2,9-bis(phenylmethyl)-1H-pyrido[3,4-b]indol-1-yl]-, methyl ester 509x 1H-Pyrido[3,4-b]indol-1-one,6-chloro-2,3,4,9-tetrahydro-9-[(4-methylphenyl)methyl]-2- propyl- 510x1H-Pyrido[3,4-b]indol-1-one,9-[3-(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)-2-hydroxypropyl]-2,3,4,9-tetrahydro-2-methyl- 511x1H-Pyrido[3,4-b]indol-1-one,9-[3-[bis(2-hydroxyethyl)amino]-2-hydroxypropyl]-2,3,4,9-tetrahydro-2-methyl- 518x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-4-hydroxy-3-(1- methylethyl)-2-(2-propen-1-yl)-,1,1-dimethylethyl ester, (3S,4S)- 519x2H-Pyrido[3,4-b]indole-2-carboxamide,1,3,4,9-tetrahydro-N-1H-indazol-3-yl-9-(2- methoxyethyl)- 521x1H-Pyrido[3,4-b]indole-2,9-dicarboxylic acid,3,4-dihydro-,2-(1,1-dimethylethyl) 9- (2,2,2-trichloroethyl) ester 523xPropanedioic acid,[2-[9-[(1,1-dimethylethoxy)carbonyl]-2,3,4,9-tetrahydro-2-(2-iodo-2-butenyl)-1H-pyrido[3,4-b]indol-1-yl]ethyl]-, dimethyl ester,(Z)- 526x1H-Pyrido[3,4-b]indol-1-one, 6-butyl-2,3,4,9-tetrahydro-2,9-bis[[4-(trifluoromethyl)phenyl]methyl]- 527x 1H-Pyrido[3,4-b]indol-1-one,6-chloro-2,3,4,9-tetrahydro-2,9-bis(3-methoxybenzoyl)- 528x1H-Pyrido[3,4-b]indole,9-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-2,3,4,9- tetrahydro- 529x1H-Pyrido[3,4-b]indole,2-[2,3:4,6-bis-O-(1-methylethylidene)-alpha-L-xylo-2-hexulofuranosonoyl]-9-(ethoxymethyl)-2,3,4,9-tetrahydro- 530x1H-Pyrido[3,4-b]indole, 2-benzoyl-2,3,4,9-tetrahydro-9-[[4-(phenylmethoxy)phenyl]methyl]- 533x 1H-Pyrido[3,4-b]indole,3-butyl-2,3,4,9-tetrahydro-9-[2-(4-pyridinyl)ethyl]- 534x1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-6-(methylsulfonyl)-9-(phenylmethyl)-2- propyl- 535x1H-Pyrido[3,4-b]indole,6-chloro-9-(3-chlorobenzoyl)-2,3,4,9-tetrahydro-2- (trifluoroacetyl)-538x 1H-Pyrido[3,4-b]indole,2-(3-chloro-4-hydroxybenzoyl)-2,3,4,9-tetrahydro-9-[[4-(trifluoromethyl)phenyl]methyl]- 540x2H-Pyrido[3,4-b]indole-2-carboxaldehyde,1,3,4,9-tetrahydro-4-oxo-9-(phenylmethyl)- 542x1H-Pyrido[3,4-b]indol-1-one,6-bromo-2,3,4,9-tetrahydro-9-(phenylmethyl)-2-propyl- 547x9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-2-[4-(1,2,4,5-tetrahydro-2-oxobenz[cd]indol-2a(3H)-yl)butyl]-, methyl ester 549x2H-Pyrido[3,4-b]indole-2-carboxaldehyde,1,3,4,9-tetrahydro-1-oxo-9-(phenylmethyl)- 550x1H-Pyrido[3,4-b]indol-1-one,6-chloro-2,3,4,9-tetrahydro-2,9-bis[(4-nitrophenyl)methyl]- 552x1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-9-[2-hydroxy-3-[(phenylmethyl)amino]propyl]-2-methyl- 555x9H-Pyrido[3,4-b]indole-9-ethanol, 1,2,3,4-tetrahydro-, acetate (ester)559x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-3-methyl-4-oxo-2-(2- propen-1-yl)-, 1,1-dimethylethylester, (3S)- 562x 2H-Pyrido[3,4-b]indole-2-carboxylic acid,9-[[(2S)-1-[[4-(1,1-dimethylpropyl)phenyl]sulfonyl]-2-pyrrolidinyl]carbonyl]-1,3,4,9-tetrahydro-1-(2-propenyl)-, 2,2,2-trichloroethyl ester, (1S)- 563x1H-Pyrido[3,4-b]indole-2,9-dicarboxylic acid,1-[[(4R)-3-ethyltetrahydro-2-(4-methoxyphenoxy)-6-oxo-2H-pyran-4-yl]methyl]-3,4-dihydro-,9-(1,1-dimethylethyl)2- (phenylmethyl) ester, (1R)- 564x 9H-Pyrido[3,4-b]indole-9-aceticacid, 1,2,3,4-tetrahydro-2-[[(3- methylphenyl)amino]carbonyl]-,1,1-dimethylethyl ester 565x 1-Butanone,1-[4-(1,1-dimethylethyl)phenyl]-4-[9-[(4-fluorophenyl)methyl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]- 567x1H-Pyrido[3,4-b]indol-1-one,6-butyl-2,9-bis[(4-chlorophenyl)methyl]-2,3,4,9-tetrahydro- 568x1H-Pyrido[3,4-b]indole-2,9-dicarboxylic acid,6-chloro-3,4-dihydro-,diethyl ester 569x9H-Pyrido[3,4-b]indole-9-propanamine,1,2,3,4-tetrahydro-N,N-dimethyl-2-[3-(3- pyridinyl)propyl]- 570x1H-Pyrido[3,4-b]indole,2-[2,3:4,6-bis-O-(1-methylethylidene)-alpha-L-xylo-2-hexulofuranosonoyl]-9-(ethoxymethyl)-2,3,4,9-tetrahydro-1-(phenylmethyl)-,(1R)- 571x 1H-Pyrido[3,4-b]indole,2-(1,3-benzodioxol-5-ylcarbonyl)-2,3,4,9-tetrahydro-9-[(4-hydroxyphenyl)methyl]- 573x 1H-Pyrido[3,4-b]indole-1-acetonitrile,2,3,4,9-tetrahydro-9-(methoxymethyl)-, (S)- 574x 1H-Pyrido[3,4-b]indole,3-heptyl-2,3,4,9-tetrahydro-6-methyl-9-[2-(6-methyl-3- pyridinyl)ethyl]-575x 1H-Pyrido[3,4-b]indol-1-one,2-[(4-bromophenyl)methyl]-2,3,4,9-tetrahydro-6-(methylsulfonyl)-9-(phenylmethyl)- 576x 1H-Pyrido[3,4-b]indole,9-(3-bromobenzoyl)-6-chloro-2,3,4,9-tetrahydro-2- (trifluoroacetyl)-577x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2-(phenylacetyl)- 579x2H-Pyrido[3,4-b]indole-2-carboxylic acid, 1,3,4,9-tetrahydro-9-[[4-(phenylmethoxy)phenyl]methyl]-, phenylmethyl ester 582x1H-Pyrido[3,4-b]indole-1-carbonitrile,1,1′-[1,4-phenylenebis(methylene)]bis[2-benzoyl-2,3,4,9-tetrahydro-9-(phenylmethyl)- 583x 1H-Pyrido[3,4-b]indol-1-one,6-bromo-2,3,4,9-tetrahydro-9-[(4-methylphenyl)methyl]-2- (phenylmethyl)-584x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,2-(5-formyl-2-pyrimidinyl)-1,2,3,4-tetrahydro-, 1,1-dimethylethyl ester588x 2H-Pyrido[3,4-b]indole-2-carboxylic acid,9-[(diethylamino)carbonyl]-1,3,4,9-tetrahydro-, 1,1-dimethylethyl ester592x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-3-methyl-4-oxo-, 1,1- dimethylethyl ester, (3S)- 593x9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-1-(4-hydroxybutyl)-2-[(4- methylphenyl)sulfonyl]-,1,1-dimethylethyl ester 599x 1H-Pyrido[3,4-b]indole,2-benzyl-9-[3-(dimethylamino)propyl]-2,3,4,9-tetrahydro-6- methoxy- 600x1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-6-methoxy-2,9-bis[(4-methylphenyl)methyl]- 601x 1H-Pyrido[3,4-b]indole,9-(2-dimethylaminoethyl)-2,3,4,9-tetrahydro-1,2-dimethyl- 603x1H-Pyrido[3,4-b]indole, 2,3,4,9-tetrahydro-2-(4-hydroxybenzoyl)-9-[(3-hydroxyphenyl)methyl]- 607x 1H-Pyrido[3,4-b]indole-1-acetic acid,9-benzyl-2,3,4,9-tetrahydro-, ethyl ester 608x1H-Pyrido[3,4-b]indol-1-one,6-butyl-2,9-bis[(3-fluorophenyl)methyl]-2,3,4,9-tetrahydro- 609x1H-Pyrido[3,4-b]indol-1-one,6-chloro-2,9-bis(2-chlorobenzoyl)-2,3,4,9-tetrahydro- 610x1H-Pyrido[3,4-b]indole,2-acetyl-9-[2-[4-(3-chlorophenyl)-1-piperazinyl]ethyl]-2,3,4,9-tetrahydro- 611x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-(methoxymethyl)- 612x 1H-Pyrido[3,4-b]indole,2-[(1,6-dihydro-6-oxo-3-pyridinyl)carbonyl]-2,3,4,9-tetrahydro-9-[(4-hydroxyphenyl)methyl]- 614x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-(methoxymethyl)-1-(2-propenyl)-, (S)- 615x1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-6-methyl-3-(2-methylpropyl)-9-[2-(6-methyl-3-pyridinyl)ethyl]- 616x 1H-Pyrido[3,4-b]indol-1-one,2-[(4-chlorophenyl)methyl]-2,3,4,9-tetrahydro-6-(methylsulfonyl)-9-(phenylmethyl)- 617x 1H-Pyrido[3,4-b]indole,6-chloro-2,3,4,9-tetrahydro-9-(4-methoxybenzoyl)-2- (trifluoroacetyl)-622x 2H-Pyrido[3,4-b]indole-2-ethanol,1,3,4,9-tetrahydro-1-methyl-beta-phenyl-9- (phenylmethyl)-, [R—(R*,R*)]-624x 1H-Pyrido[3,4-b]indol-1-one,2,9-bis[(4-bromophenyl)methyl]-2,3,4,9-tetrahydro-6- (trifluoromethoxy)-625x 5-Pyrimidinecarboxylic acid,2-[1,3,4,9-tetrahydro-9-[2-(1-piperidinyl)ethyl]-2H-pyrido[3,4-b]indol-2-yl]- 626x 1H-Pyrido[3,4-b]indole,2-(cyclohexylcarbonyl)-2,3,4,9-tetrahydro-9-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- 629x2H-Pyrido[3,4-b]indole-2-carboxylic acid,9-(aminocarbonyl)-1,3,4,9-tetrahydro-, 1,1- dimethylethyl ester 630x9H-Pyrido[3,4-b]indole-9-propanoic acid,2-[(1,1-dimethylethoxy)carbonyl]-1,2,3,4- tetrahydro-, ethyl ester 631x1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-(methoxymethyl)-1-(phenylmethyl)-, (S)- 633x9H-Pyrido[3,4-b]indole-9-carboxylic acid,4-(1,1-dimethylethyl)-1,2,3,4-tetrahydro-4- hydroxy-3-methyl-,1,1-dimethylethyl ester, (3S,4S)- 634x 1H-Pyrido[3,4-b]indole,2-(4-chlorobenzoyl)-9-[(4-cyanophenyl)methyl]-2,3,4,9- tetrahydro- 639x1H-Pyrido[3,4-b]indole, 9-(2-butoxyethyl)-2,3,4,9-tetrahydro-3-methyl-640x 9H-Pyrido[3,4-b]indole-9-propanamine,2-acetyl-N,N-diethyl-1,2,3,4-tetrahydro-6- methoxy- 641x1H-Pyrido[3,4-b]indol-1-one,2-benzoyl-9-[(4-bromophenyl)methyl]-2,3,4,9-tetrahydro- 6-methoxy- 642x1H-Pyrido[3,4-b]indole, 9-benzyl-2,3,4,9-tetrahydro-1,2-dimethyl- 643x2H-Pyrido[3,4-b]indole-2-carboxaldehyde, 1,3,4,9-tetrahydro-9-[(4-methoxyphenyl)methyl]-4-oxo- 644x Benzoic acid,4-[[1,2,3,4-tetrahydro-2-(4-hydroxybenzoyl)-9H-pyrido[3,4-b]indol-9-yl]methyl]- 645x 9H-Pyrido[3,4-b]indole-9-acetamide,1,2,3,4-tetrahydro-N-methyl-2-[4-[(2aS)-1,2,4,5-tetrahydro-2-oxobenz[cd]indol-2a(3H)-yl]butyl]- 646x9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-3-(1-methylpropyl)-4-oxo- 2-(phenylsulfonyl)-,1,1-dimethylethyl ester, [S—(R*,R*)]- 648x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-2-methyl-6-[(1,2,3,4-tetrahydro-2-methyl-9H-pyrido[3,4-b]indol-9-yl)methyl]- 649x 1H-Pyrido[3,4-b]indol-1-one,6-butyl-9-[(4-chlorophenyl)methyl]-2,3,4,9-tetrahydro-2-(2-propen-1-yl)- 650x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,6-chloro-1,2,3,4-tetrahydro-2-(trifluoroacetyl)-, phenyl ester 651x1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-[3-(1-piperidinyl)propyl]-2-[3-(3-pyridinyl)propyl]- 653x 1H-Pyrido[3,4-b]indole,2-(4-aminobenzoyl)-2,3,4,9-tetrahydro-9-[(4- hydroxyphenyl)methyl]- 655x1H-Pyrido[3,4-b]indole, 2,3,4,9-tetrahydro-9-(methoxymethyl)-2-(1-naphthalenylcarbonyl)-1-(2-propenyl)-, (S)- 656x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-3-(3-methylbutyl)-9-[2-(6-methyl-3- pyridinyl)ethyl]-657x 1H-Pyrido[3,4-b]indol-1-one,9-[(4-bromophenyl)methyl]-2,3,4,9-tetrahydro-2-(1-methylethyl)-6-(methylsulfonyl)- 658x2H-Pyrido[3,4-b]indole-2-carboxylic acid,6-chloro-1,3,4,9-tetrahydro-9-(phenylmethyl)-, ethyl ester 659x9H-Pyrido[3,4-b]indole-9-carboxylic acid, 2-[[3-bromo-1-[(1,1-dimethylethoxy)carbonyl]-1H-indol-2-yl]methyl]-1,2,3,4-tetrahydro-3-(hydroxymethyl)-4-oxo-, 1,1-dimethylethyl ester, (3S)- 661x2H-Pyrido[3,4-b]indole-2-carboxylic acid, 1,3,4,9-tetrahydro-9-[[4-(methoxycarbonyl)phenyl]methyl]-, phenylmethyl ester 663x1H-Pyrido[3,4-b]indole-1-propanoic acid,2,3,4,9-tetrahydro-2-methyl-9-(phenylmethyl)- 665x1H-Pyrido[3,4-b]indol-1-one,2,9-bis[(4-fluorophenyl)methyl]-2,3,4,9-tetrahydro-6-(trifluoromethoxy)- 667x 1H-Pyrido[3,4-b]indol-1-one,9-benzyl-2-[3-(dimethylamino)propyl]-2,3,4,9-tetrahydro- 6-methoxy- 670x9H-Pyrido[3,4-b]indole-9-acetic acid,2-[(1,1-dimethylethoxy)carbonyl]-1,2,3,4- tetrahydro-, methyl ester 673x1H-pyrido[1,2-a][1,5]diazocin-8(2H)-one,3-(3-(2-methyl-1-oxo-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-2-hydroxypropyl)-1,5-methano-3,4,5,6-tetrahydro-,(1R,5S)- 674x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-4-hydroxy-3-(1- methylethyl)-4-(2-propen-1-yl)-,1,1-dimethylethyl ester, (3S,4S)- 675x 1H-Pyrido[3,4-b]indole,9-(2-butynyl)-2-(4-chlorobenzoyl)-2,3,4,9-tetrahydro- 679xBenzeneacetamide,alpha-cyclopentyl-N-(2-hydroxy-1-phenylethyl)-4-[(1,2,3,4-tetrahydro-2-methyl-1-oxo-9H-pyrido[3,4-b]indol-9-yl)methyl]-,[R—(R*,R*)]-680x 1H-Pyrido[3,4-b]indole-1,3(2H)-dione,4,9-dihydro-2-methyl-9-(phenylmethyl)- 681x 1H-Pyrido[3,4-b]indol-1-one,9-benzyl-2-[2-(dimethylamino)ethyl]-2,3,4,9-tetrahydro- 682x1H-Pyrido[3,4-b]indol-1-one,9-[(4-bromophenyl)methyl]-2,3,4,9-tetrahydro-6-methoxy- 2-propyl- 683x9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-1-methyl-,1,1-dimethylethyl ester, (1S)- 684x1H-Pyrido[3,4-b]indole, 9-[(4-fluorophenyl)methyl]-2,3,4,9-tetrahydro-685x Benzoic acid,4-[[1,3,4,9-tetrahydro-9-[(4-hydroxyphenyl)methyl]-2H-pyrido[3,4-b]indol-2-yl]carbonyl]-, methyl ester 688x 1H-Pyrido[3,4-b]indole,2-acetyl-2,3,4,9-tetrahydro-9-[(pentafluorophenyl)methyl]- 689x1H-Pyrido[3,4-b]indol-1-ol,9-[2-(dimethylamino)ethyl]-2,3,4,9-tetrahydro- 690x1H-Pyrido[3,4-b]indol-1-one,2,9-bis[(4-bromophenyl)methyl]-2,3,4,9-tetrahydro-6- (methylthio)- 691x1H-Pyrido[3,4-b]indole,6-chloro-2,3,4,9-tetrahydro-9-(3-nitrobenzoyl)-2- (trifluoroacetyl)-694x 1H-Pyrido[3,4-b]indole,2-(3-chloro-4-hydroxybenzoyl)-2,3,4,9-tetrahydro-9-[(4-hydroxyphenyl)methyl]- 696x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-2-(1-oxo-2-butenyl)-1-(4- oxo-2-butenyl)-, methylester, (E,E)- 697x 9H-Pyrido[3,4-b]indole-9-propanamine,1,2,3,4-tetrahydro-N,N-dimethyl- 698x 1H-Pyrido[3,4-b]indol-1-one,6-bromo-2,3,4,9-tetrahydro-2,9-bis(phenylmethyl)- 700x9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-3-(1-methylethyl)-4-oxo-, 1,1-dimethylethyl ester,(3S)- 702x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-2,3-dimethyl-4-phenyl-9-(phenylmethyl)- 704x1H-Pyrido[3,4-b]indole,1-[2-(1,3-dioxolan-2-yl)ethyl]-2,3,4,9-tetrahydro-2-methyl-9-(phenylmethyl)- 706x 1H-Pyrido[3,4-b]indol-1-one,2,9-bis[(4-bromophenyl)methyl]-6-chloro-2,3,4,9- tetrahydro- 708x1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2-methyl-9-(3-phenylpropyl)- 711x9H-Pyrido[3,4-b]indole-9-acetamide, 1,2,3,4-tetrahydro-N-methyl- 715x9H-Pyrido[3,4-b]indole-9-carboxylic acid,4-(3-buten-1-yl)-1,2,3,4-tetrahydro-4-hydroxy- 3-(1-methylethyl)-,1,1-dimethylethyl ester, (3S,4S)- 716x 1H-Pyrido[3,4-b]indole,9-benzyl-2,3,4,9-tetrahydro-2-p-tolylsulfonyl- 717x2H-Pyrido[3,4-b]indole-2-carboxylic acid,1,3,4,9-tetrahydro-1-(1-methylethyl)-9- (phenylmethyl)-,(1R,2S,5R)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyl ester, (1S)-719x 9H-Pyrido[3,4-b]indole-9-carboxamide,N,N-diethyl-1,2,3,4-tetrahydro- 720x Benzeneacetamide,alpha-cyclopentyl-N-(2-hydroxy-1-phenylethyl)-4-[(1,2,3,4-tetrahydro-2-methyl-1-oxo-9H-pyrido[3,4-b]indol-9-yl)methyl]-,[R—(R*,S*)]-721x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-2-methyl-9-(phenylmethyl)- 722x1H-Pyrido[3,4-b]indol-1-one, 9-benzyl-2,3,4,9-tetrahydro-6-methoxy-2-(3-piperidinopropyl)- 723x 1H-Pyrido[3,4-b]indol-1-one,2-butyl-2,3,4,9-tetrahydro-6-methoxy-9-(phenylmethyl)- 725x1H-Pyrido[3,4-b]indol-1-one,9-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropyl]-2,3,4,9-tetrahydro-2-methyl- 726x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-2-(4-hydroxy-3-methylbenzoyl)-9-[(4-hydroxyphenyl)methyl]- 728x 1H-Pyrido[3,4-b]indole-2,9-dicarboxylicacid, 3,4-dihydro-4-hydroxy-4-propyl-, bis(1,1- dimethylethyl) ester730x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-[2-(6-methyl-3-pyridinyl)ethyl]-3-propyl- 731x1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2,9-bis[(4-methylphenyl)methyl]-6- (methylsulfonyl)-732x 1H-Pyrido[3,4-b]indole,6-chloro-9-(4-cyanobenzoyl)-2,3,4,9-tetrahydro-2- (trifluoroacetyl)-733x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,1-ethyl-1,2,3,4-tetrahydro-2-propyl-, methyl ester 735x1H-Pyrido[3,4-b]indole,2-(4-chloro-2-hydroxybenzoyl)-2,3,4,9-tetrahydro-9-[(4-hydroxyphenyl)methyl]- 738x 1H-Pyrido[3,4-b]indol-1-one,2-butyl-2,3,4,9-tetrahydro-9-(phenylmethyl)- 739x1H-Pyrido[3,4-b]indol-1-one,6-bromo-2,3,4,9-tetrahydro-2,9-bis[(4-nitrophenyl)methyl]- 744xBenz[cd]indol-2(1H)-one,2a,3,4,5-tetrahydro-2a-[4-[1,3,4,9-tetrahydro-9-(phenylmethyl)-2H-pyrido[3,4-b]indol-2-yl]butyl]- 746x1H-Pyrido[3,4-b]indol-1-one,2,9-bis[2-(dimethylamino)ethyl]-2,3,4,9-tetrahydro-6- methoxy- 747x1H-Pyrido[3,4-b]indol-1-one,2-[(4-bromophenyl)methyl]-6-chloro-2,3,4,9-tetrahydro-9-[(4-methylphenyl)methyl]- 749x 1H-Pyrido[3,4-b]indol-1-one,9-[3-(diethylamino)-2-hydroxypropyl]-2,3,4,9-tetrahydro-2- methyl- 752x2H-Pyrido[3,4-b]indole-2-carboxylic acid,9-[2-(dimethylamino)-2-oxoethyl]-1,3,4,9- tetrahydro-, 1,1-dimethylethylester 755x 1H-Pyrido[3,4-b]indol-1-one,6-chloro-2-[2-(diethylamino)ethyl]-2,3,4,9-tetrahydro-9- phenethyl- 756x9H-Pyrido[3,4-b]indole-9-carboxylic acid,1,2,3,4-tetrahydro-4-hydroxy-3-(1- methylethyl)-2-(phenylsulfonyl)-,1,1-dimethylethyl ester, (3S,4S)- 757x 1H-Pyrido[3,4-b]indole,9-(2-ethoxyethyl)-2,3,4,9-tetrahydro-3-methyl- 758x1H-Pyrido[3,4-b]indole-2,9-dicarboxylic acid,4-[2-(4-chlorophenyl)-2-oxoethyl]-3,4- dihydro-, bis(1,1-dimethylethyl)ester 759x 9H-Pyrido[3,4-b]indole-9-carboxylic acid,2-[[3-(1,1-dimethylethoxy)-3-oxo-2-[1-[(phenylmethoxy)carbonyl]-4-piperidinyl]propyl]sulfonyl]-1,2,3,4-tetrahydro-,2,2,2- trichloroethyl ester 761x 4H-Pyrido[3,4-b]indol-4-one,1,2,3,9-tetrahydro-9-(phenylmethyl)- 762x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-(methoxymethyl)-1-[(3- methoxyphenyl)methyl]-, (S)-764x 1H-Pyrido[3,4-b]indol-1-one,2-[(4-bromophenyl)methyl]-2,3,4,9-tetrahydro-6-methoxy-9-(phenylmethyl)- 765x 1H-Pyrido[3,4-b]indol-1-one,6-chloro-2,9-bis(3-chlorobenzoyl)-2,3,4,9-tetrahydro- 767x1H-Pyrido[3,4-b]indole,2-(2,4-dihydroxy-3,6-dimethylbenzoyl)-2,3,4,9-tetrahydro-9-[(4-hydroxyphenyl)methyl]- 770x 1H-Pyrido[3,4-b]indol-1-one,9-[2-[bis(phenylmethyl)amino]ethyl]-2,3,4,9-tetrahydro-6-methoxy-2-methyl- 771x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-3-(1-methylpropyl)-9-[2-(6-methyl-3-pyridinyl)ethyl]- 772x 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-9-[(4-methylphenyl)methyl]-6-(methylsulfonyl)-2-propyl- 773x 1H-Pyrido[3,4-b]indole,6-chloro-2,3,4,9-tetrahydro-2-(trifluoroacetyl)-9-[3-(trifluoromethoxy)benzoyl]- 774x 1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-9-[[4-(trifluoromethyl)phenyl]methyl]- 776x1H-Pyrido[3,4-b]indole,2-(3-chloro-4-hydroxybenzoyl)-9-[(4-fluorophenyl)methyl]-2,3,4,9-tetrahydro- 779x 1H-Pyrido[3,4-b]indole-1-carbonitrile,2,9-dibenzoyl-2,3,4,9-tetrahydro- 780x 1H-Pyrido[3,4-b]indol-1-one,6-bromo-2,9-bis[(4-fluorophenyl)methyl]-2,3,4,9- tetrahydro- 782x1H-Pyrido[3,4-b]indole, 2,3,4,9-tetrahydro-9-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-2-(1-oxo-2-propenyl)- 785x9H-Pyrido[3,4-b]indole-9-carboxamide,1,2,3,4-tetrahydro-N,N-dimethyl-2-[4-(1,2,4,5-tetrahydro-2-oxobenz[cd]indol-2a(3H)-yl)butyl]- 788x1H-Pyrido[3,4-b]indol-1-one,6-fluoro-2,3,4,9-tetrahydro-2,9-bis(phenylmethyl)- 789x1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-9-[2-hydroxy-3-(1-pyrrolidinyl)propyl]- 2-methyl-793x 9H-Pyrido[3,4-b]indole-9-acetamide,1,2,3,4-tetrahydro-N,N-dimethyl-2-[4-(1,2,4,5-tetrahydro-2-oxobenz[cd]indol-2a(3H)-yl)butyl]-

TABLE 1A No Name 450z 9H-Pyrido[3,4-b]indole-9-acetic acid,2-[(4-fluorophenyl)sulfonyl]-1,2,3,4- tetrahydro- 451z1H-Pyrido[3,4-b]indole,2,3,4,9-tetrahydro-1-phenyl-9-(phenylmethyl)-,(S)-(9CI) 452z9H-Pyrido[3,4-b]indole-9-propanoic acid,2-[(1,1-dimethylethoxy)carbonyl]-1,2,3,4- tetrahydro- 453z2H-Pyrido[3,4-b]indole-2-ethanol, 1,3,4,9-tetrahydro-beta,1-diphenyl-9-(phenylmethyl)-, [S—(R*,S*)]-(9CI) 454z 9H-Pyrido[3,4-b]indole-9-aceticacid, 2-[(1,1-dimethylethoxy)carbonyl]-1,2,3,4- tetrahydro- 455z9H-Pyrido[3,4-b]indole-9-acetic acid,1,2,3,4-tetrahydro-2-(phenylsulfonyl)- 456z1H-Pyrido[3,4-b]indole-5-carboxylic acid, 2,3,4,9-tetrahydro-4-oxo-2,9-bis(phenylmethyl)-, methyl ester 457z 1H-Pyrido[3,4-b]indol-1-one,9-[3-(dimethylamino)propyl]-2,3,4,9-tetrahydro- 458z1H-Pyrido[3,4-b]indol-1-one,6-chloro-9-[3-(dimethylamino)propyl]-2,3,4,9- tetrahydro- 459z1H-Pyrido[3,4-b]indol-1-one,6-chloro-2,3,4,9-tetrahydro-9-[3-(4-methyl-1- piperazinyl)propyl]- 460z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-6-(phenylmethoxy)-9-[2-(1- piperidinyl)ethyl]- 461z1H-Pyrido[3,4-b]indol-1-one,9-[3-(butylamino)propyl]-6-chloro-2,3,4,9-tetrahydro- 462z1H-Pyrido[3,4-b]indol-1-one,9-[2-(dimethylamino)ethyl]-2,3,4,9-tetrahydro-6- methoxy- 463z1H-Pyrido[3,4-b]indol-1-one,6-chloro-9-[2-(diethylamino)ethyl]-2,3,4,9-tetrahydro- 464z1H-Pyrido[3,4-b]indol-1-one,6-chloro-2,3,4,9-tetrahydro-9-[3-[4-(2-hydroxyethyl)-1-piperazinyl]propyl]- 465z 1H-Pyrido[3,4-b]indol-1-one,9-[3-(dimethylamino)propyl]-2,3,4,9-tetrahydro-7- methoxy- 466z1H-Pyrido[3,4-b]indol-1-one,9-[3-(dimethylamino)propyl]-2,3,4,9-tetrahydro-6- methoxy- 467z1H-Pyrido[3,4-b]indol-1-one,9-[3-(dimethylamino)propyl]-2,3,4,9-tetrahydro-6- (phenylmethoxy)- 468z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-9-(2-oxo-2-phenylethyl)-6- (phenylmethoxy)- 469z1H-Pyrido[3,4-b]indol-1-one,6-chloro-2,3,4,9-tetrahydro-9-[3-(1-piperidinyl)propyl]- 470z1H-Pyrido[3,4-b]indol-1-one,9-[2-(diethylamino)ethyl]-2,3,4,9-tetrahydro-6- (phenylmethoxy)- 471z1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-6-methoxy-9-[3-(1-pyrrolidinyl)propyl]- 472z 1H-Pyrido[3,4-b]indol-1-one,9-[2-(dimethylamino)ethyl]-2,3,4,9-tetrahydro-6- hydroxy- 473z1H-Pyrido[3,4-b]indol-1-one,9-[3-(diethylamino)propyl]-2,3,4,9-tetrahydro-6- methoxy- 474z1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-6-methoxy-9-[3-(1-piperidinyl)propyl]- 475z 9H-Pyrido[3,4-b]indole-9-acetamide,1,2,3,4-tetrahydro-1-oxo-N-phenyl- 476z 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-6-hydroxy-9-[2-(1- piperidinyl)ethyl]- 477z1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-6-methoxy-9-[3-(4-morpholinyl)propyl]- 478z 1H-Pyrido[3,4-b]indol-1-one,9-[2-(dimethylamino)-1-methylethyl]-2,3,4,9-tetrahydro-6-(phenylmethoxy)- 479z1H-Pyrido[3,4-b]indole-2,9-dipropanenitrile,3,4-dihydro-7-methoxy-1-methyl-480z 1H-Pyrido[3,4-b]indol-1-one,9-[3-(dimethylamino)propyl]-2,3,4,9-tetrahydro-6- methyl- 481z1H-Pyrido[3,4-b]indol-1-one,9-[(4-fluorophenyl)methyl]-2,3,4,9-tetrahydro-6- methoxy- 482z1H-Pyrido[3,4-b]indol-1-one,6-acetyl-9-[2-(dimethylamino)ethyl]-2,3,4,9-tetrahydro- 483z1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-6-methoxy-9-[(4-methylphenyl)methyl]- 484z 1H-Pyrido[3,4-b]indole-6-carboxylicacid,9-[3-(dimethylamino)propyl]-2,3,4,9- tetrahydro-1-oxo-, ethyl ester485z 1H-Pyrido[3,4-b]indol-1-one,9-[(4-bromophenyl)methyl]-2,3,4,9-tetrahydro-6- methoxy- 486z1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-6-methoxy-9-[(4-nitrophenyl)methyl]- 487z 1H-Pyrido[3,4-b]indol-1-one,9-[(4-chlorophenyl)methyl]-2,3,4,9-tetrahydro-6- methoxy- 488z1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-6-methoxy-9-[[4-(trifluoromethyl)phenyl]methyl]- 489z 1H-Pyrido[3,4-b]indol-1-one,6-bromo-9-[3-(dimethylamino)propyl]-2,3,4,9- tetrahydro- 490z1H-Pyrido[3,4-b]indol-1-one,9-[(4-bromophenyl)methyl]-6-butyl-2,3,4,9-tetrahydro- 491z1H-Pyrido[3,4-b]indol-1-one,9-[3-(dimethylamino)propyl]-6-fluoro-2,3,4,9- tetrahydro- 492z1H-Pyrido[3,4-b]indol-1-one, 6-butyl-2,3,4,9-tetrahydro-9-[[4-(trifluoromethyl)phenyl]methyl]- 493z2H-Pyrido[3,4-b]indole-2-carboxylicacid,9-(cyanomethyl)-1,3,4,9-tetrahydro-, 1,1- dimethylethyl ester 494z1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-9-(phenylmethyl)- 495z1H-Pyrido[3,4-b]indol-1-one,6-butyl-9-[(4-chlorophenyl)methyl]-2,3,4,9-tetrahydro- 496z9H-Pyrido[3,4-b]indole-9-acetamide,1,2,3,4-tetrahydro-6-methoxy-N-[4-(1- methylethoxy)phenyl]-1-oxo- 497z9H-Pyrido[3,4-b]indole-9-acetonitrile,1,2,3,4-tetrahydro-2-[4-(1,2,4,5-tetrahydro-2-oxobenz[cd]indol-2a(3H)-yl)butyl]- 498z 1H-Pyrido[3,4-b]indol-1-one,6-acetyl-9-[3-(dimethylamino)propyl]-2,3,4,9- tetrahydro- 499z1H-Pyrido[3,4-b]indol-1-one,6-butyl-9-[(3-fluorophenyl)methyl]-2,3,4,9-tetrahydro- 500z1H-Pyrido[3,4-b]indol-1-one,9-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-2,3,4,9-tetrahydro-6-methoxy- 501z 1H-Pyrido[3,4-b]indol-1-one,9-[3-(dimethylamino)propyl]-2,3,4,9-tetrahydro-8- (trifluoromethyl)-502z 1H-Pyrido[3,4-b]indol-1-one,6-butyl-2,3,4,9-tetrahydro-9-[(4-nitrophenyl)methyl]- 503z1H-Pyrido[3,4-b]indol-1-one,6-bromo-2,3,4,9-tetrahydro-9-(phenylmethyl)- 504z1H-Pyrido[3,4-b]indol-1-one,6-butyl-9-[(4-fluorophenyl)methyl]-2,3,4,9-tetrahydro- 505z1H-Pyrido[3,4-b]indol-1-one,6-bromo-2,3,4,9-tetrahydro-9-(2-methoxyethyl)- 506z1H-Pyrido[3,4-b]indol-1-one,6-butyl-2,3,4,9-tetrahydro-9-[(4-methylphenyl)methyl]- 507z9H-Pyrido[3,4-b]indole-9-carboxylicacid,6-bromo-1,2,3,4-tetrahydro-1-oxo-, 1,1- dimethylethyl ester 508z1H-Pyrido[3,4-b]indol-1-one, 6-bromo-9-[(4-bromophenyl)methyl]-2,3,4,9-tetrahydro- 509z 9H-Pyrido[3,4-b]indole-9-acetic acid,6-bromo-1,2,3,4-tetrahydro-1-oxo-,methyl ester 510z1H-Pyrido[3,4-b]indol-1-one,8-chloro-9-[3-(dimethylamino)propyl]-2,3,4,9- tetrahydro- 511z1H-Pyrido[3,4-b]indol-1-one, 6-bromo-2,3,4,9-tetrahydro-9-[[4-(trifluoromethyl)phenyl]methyl]- 512z 9H-Pyrido[3,4-b]indole-9-aceticacid, 6-bromo-1,2,3,4-tetrahydro-1-oxo- 513z1H-Pyrido[3,4-b]indol-1-one,6-bromo-2,3,4,9-tetrahydro-9-[(4-nitrophenyl)methyl]- 514z9H-Pyrido[3,4-b]indole-9-acetamide, 6-bromo-1,2,3,4-tetrahydro-1-oxo-515z 1H-Pyrido[3,4-b]indol-1-one, 6-bromo-2,3,4,9-tetrahydro-9-[(4-methylphenyl)methyl]- 516z 1H-Pyrido[3,4-b]indol-1-one,6-bromo-2,3,4,9-tetrahydro-9-(2-methoxyacetyl)- 517z1H-Pyrido[3,4-b]indol-1-one,9-[3-(dimethylamino)propyl]-2,3,4,9-tetrahydro-6- (trifluoromethyl)-518z 1H-Pyrido[3,4-b]indol-1-one,6-bromo-9-[(3-fluorophenyl)methyl]-2,3,4,9- tetrahydro- 519z1H-Pyrido[3,4-b]indol-1-one,9-[2-(acetyloxy)acetyl]-6-bromo-2,3,4,9-tetrahydro- 520z1H-Pyrido[3,4-b]indol-1-one, 6-bromo-9-[(2-fluorophenyl)methyl]-2,3,4,9-tetrahydro- 521z 1H-Pyrido[3,4-b]indol-1-one,6-bromo-9-(cyclohexylcarbonyl)-2,3,4,9-tetrahydro- 522z1H-Pyrido[3,4-b]indol-1-one, 6-bromo-9-[(4-fluorophenyl)methyl]-2,3,4,9-tetrahydro- 523z 1H-Pyrido[3,4-b]indol-1-one,9-[2-(3,4-dihydro-2(1H)-isoquinolinyl)ethyl]-2,3,4,9- tetrahydro- 524z1H-Pyrido[3,4-b]indole-6-sulfonamide,9-[2-(diethylamino)ethyl]-2,3,4,9-tetrahydro-N,N-dimethyl-1-oxo- 525z 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-9-[(4-methylphenyl)methyl]-6- (methylthio)- 526z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-9-[2-[4-(2-methoxyphenyl)-1- piperazinyl]ethyl]- 527z1H-Pyrido[3,4-b]indol-1-one,6-chloro-9-[3-(dimethylamino)-2-methylpropyl]- 2,3,4,9-tetrahydro- 528z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-9-[(4-methylphenyl)methyl]-6- (methylsulfonyl)- 529z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-9-[2-[4-(2-pyrimidinyl)-1- piperazinyl]ethyl]- 530z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-6-(trifluoromethoxy)-9-[[4-(trifluoromethyl)phenyl]methyl]- 531z 1H-Pyrido[3,4-b]indol-1-one,9-[3-(3,4-dihydro-2(1H)-isoquinolinyl)propyl]-2,3,4,9- tetrahydro- 532z1H-Pyrido[3,4-b]indol-1-one,6-chloro-2,3,4,9-tetrahydro-9-[2-methyl-3-(1- piperidinyl)propyl]- 533z1H-Pyrido[3,4-b]indol-1-one,9-[(4-fluorophenyl)methyl]-2,3,4,9-tetrahydro-6- (trifluoromethoxy)-534z 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-9-[3-[4-(2-methoxyphenyl)-1- piperazinyl]propyl]-535z 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-6-(methylthio)-9-[[4-(trifluoromethyl)phenyl]methyl]- 536z 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-9-[3-[4-(2-pyrimidinyl)-1- piperazinyl]propyl]- 537z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-6-(methylsulfonyl)-9-[[4-(trifluoromethyl)phenyl]methyl]- 538z 1H-Pyrido[3,4-b]indol-1-one,9-[2-(dimethylamino)ethyl]-2,3,4,9-tetrahydro- 539z1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-6-(methylsulfonyl)-9-(phenylmethyl)- 540z1H-Pyrido[3,4-b]indole-6-carbonitrile,2,3,4,9-tetrahydro-9-[2-methyl-3-(1-piperidinyl)propyl]-1-oxo- 541z 1H-Pyrido[3,4-b]indol-1-one,9-[(4-bromophenyl)methyl]-6-chloro-2,3,4,9- tetrahydro- 542z1H-Pyrido[3,4-b]indol-1-one,9-[2-(dimethylamino)ethyl]-2,3,4,9-tetrahydro-7- methoxy- 543z1H-Pyrido[3,4-b]indol-1-one, 6-chloro-2,3,4,9-tetrahydro-9-[(4-methylphenyl)methyl]- 544z 1H-Pyrido[3,4-b]indol-1-one,9-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-2,3,4,9- tetrahydro- 545z1H-Pyrido[3,4-b]indol-1-one,6-chloro-9-[(4-fluorophenyl)methyl]-2,3,4,9- tetrahydro- 546z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-6-methoxy-9-(phenylmethyl)- 547z1H-Pyrido[3,4-b]indol-1-one,6-chloro-2,3,4,9-tetrahydro-9-(phenylmethyl)- 548z1H-Pyrido[3,4-b]indol-1-one, 5-acetyl-2,3,4,9-tetrahydro-6-methoxy-9-(phenylmethyl)- 549z 1H-Pyrido[3,4-b]indol-1-one,8-chloro-9-[3-(dimethylamino)propyl]-2,3,4,9-tetrahydro-5-(trifluoromethyl)- 550z 1H-Pyrido[3,4-b]indol-1-one,6-chloro-2,3,4,9-tetrahydro-9-[[4- (trifluoromethyl)phenyl]methyl]- 551z1H-Pyrido[3,4-b]indol-1-one,9-[2-(dimethylamino)ethyl]-2,3,4,9-tetrahydro-3- methyl- 552z1H-Pyrido[3,4-b]indol-1-one,6-fluoro-2,3,4,9-tetrahydro-9-(phenylmethyl)- 553z1H-Pyrido[3,4-b]indol-1-one,9-[3-(dimethylamino)propyl]-2,3,4,9-tetrahydro-6- nitro- 554z1H-Pyrido[3,4-b]indole-6-carbonitrile,9-[3-(dimethylamino)-2-methylpropyl]-2,3,4,9-tetrahydro-1-oxo- 555z1H-Pyrido[3,4-b]indole-6-carbonitrile,9-[3-(dimethylamino)propyl]-2,3,4,9-tetrahydro-1-oxo- 556z 1H-Pyrido[3,4-b]indol-1-one,6-acetyl-2,3,4,9-tetrahydro-9-(phenylmethyl)- 557z1H-Pyrido[3,4-b]indole-6-carboxylicacid,2,3,4,9-tetrahydro-1-oxo-9-(phenylmethyl)-, ethyl ester 558zBenzeneacetamide,alpha-cyclopentyl-N-(phenylmethyl)-4-[(1,2,3,4-tetrahydro-1-oxo-9H-pyrido[3,4-b]indol-9-yl)methyl]- 559z1H-Pyrido[3,4-b]indol-1-one,9-[2-[4-(3-chlorophenyl)-1-piperazinyl]ethyl]-2,3,4,9- tetrahydro- 560zBenzeneacetamide,alpha-cyclopentyl-N-(2-hydroxy-1-phenylethyl)-4-[(1,2,3,4-tetrahydro-1-oxo-9H-pyrido[3,4-b]indol-9-yl)methyl]- 561zBenzeneacetamide,alpha-cyclopentyl-N-(2-hydroxy-1-phenylethyl)-4-[(1,2,3,4-tetrahydro-5,7-dimethyl-1-oxo-9H-pyrido[3,4-b]indol-9-yl)methyl]- 562zBenzeneacetamide,alpha-cyclopentyl-N-(phenylmethyl)-4-[(1,2,3,4-tetrahydro-5,7-dimethyl-1-oxo-9H-pyrido[3,4-b]indol-9-yl)methyl]- 563z9H-Pyrido[3,4-b]indole-9-carboxylicacid,1,2,3,4-tetrahydro-6-methoxy-4,4- dimethyl-1-oxo-,1,1-dimethylethyl ester 564z Benzeneacetic acid,alpha-cyclopentyl-4-[(1,2,3,4-tetrahydro-1-oxo-9H-pyrido[3,4-b]indol-9-yl)methyl]-, 1,1-dimethylethyl ester 565z Benzeneacetic acid,alpha-cyclopentyl-4-[(1,2,3,4-tetrahydro-5,7-dimethyl-1-oxo-9H-pyrido[3,4-b]indol-9-yl)methyl]-, 1,1-dimethylethylester 566zBenzeneacetic acid,alpha-cyclopentyl-4-[(1,2,3,4-tetrahydro-1-oxo-9H-pyrido[3,4-b]indol-9-yl)methyl]- 567z Benzeneacetic acid,alpha-cyclopentyl-4-[(1,2,3,4-tetrahydro-5,7-dimethyl-1-oxo-9H-pyrido[3,4-b]indol-9-yl)methyl]- 568z 1H-Pyrido[3,4-b]indol-1-one,9-(2-aminoethyl)-2,3,4,9-tetrahydro-6-methoxy- 569z1H-Pyrido[3,4-b]indol-1-one,9-[2-(diethylamino)ethyl]-2,3,4,9-tetrahydro-6- hydroxy- 570z1H-Pyrido[3,4-b]indol-1-one,9-(2-aminoethyl)-6-cyclohexyl-2,3,4,9-tetrahydro- 571z1H-Pyrido[3,4-b]indol-1-one,9-[2-(cyclohexylamino)ethyl]-2,3,4,9-tetrahydro-6- methoxy- 572z1H-Pyrido[3,4-b]indol-1-one,6-cyclohexyl-9-[2-(dimethylamino)ethyl]-2,3,4,9- tetrahydro- 573z1H-Pyrido[3,4-b]indol-1-one,9-[2-(dimethylamino)-1-methylethyl]-2,3,4,9- tetrahydro-6-hydroxy- 574z1H-Pyrido[3,4-b]indol-1-one,9-[3-(dimethylamino)propyl]-2,3,4,9-tetrahydro-6- hydroxy- 575z1H-Pyrido[3,4-b]indol-1-one,9-[2-(dimethylamino)ethyl]-2,3,4,9-tetrahydro-6- (phenylmethoxy)- 576z9H-Pyrido[3,4-b]indole-9-acetamide,1,2,3,4-tetrahydro-6-methoxy-1-oxo-N-phenyl-577z 1H-Pyrido[3,4-b]indol-1-one,9-[2-[bis(phenylmethyl)amino]ethyl]-2,3,4,9- tetrahydro-6-methoxy- 578z1H-Pyrido[3,4-b]indol-1-one,9-[2-[bis(phenylmethyl)amino]ethyl]-6-cyclohexyl- 2,3,4,9-tetrahydro-579z 1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-6-methoxy-9-[2-[(phenylmethyl)amino]ethyl]- 580z 1H-Pyrido[3,4-b]indol-1-one,6-[2-(diethylamino)ethoxy]-9-[2-(diethylamino)ethyl]-2,3,4,9-tetrahydro- 581z 9H-Pyrido[3,4-b]indole-9-aceticacid,alpha-ethyl-1,2,3,4-tetrahydro-1-oxo-6- (phenylmethoxy)-, ethylester 582z9H-Pyrido[3,4-b]indole-9-acetonitrile,2-(2,5-dioxo-1-phenyl-3-pyrrolidinyl)-1,2,3,4-tetrahydro- 583z (1R,3S)-benzyl2-acetyl-9-benzyl-6-methyl-1-((1-adamantyl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate 584z1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-8-methyl-2-phenyl-9-(phenylmethyl)- 585z 1H-Pyrido[3,4-b]indol-1-one,6-bromo-2-butyl-2,3,4,9-tetrahydro-9-(phenylmethyl)- 586z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-2-methyl-6-nitro-1-oxo-, methyl ester 587z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-6,8-dimethyl-1-oxo-2- phenyl- 588z1H-Pyrido[3,4-b]indol-1-one,2-butyl-2,3,4,9-tetrahydro-6-nitro-9-(phenylmethyl)- 589z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-2-methyl-8-nitro-1-oxo- 590z9H-Pyrido[3,4-b]indole-9-acetic acid,2-butyl-1,2,3,4-tetrahydro-1-oxo-,methyl ester 591z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-7,8-dimethyl-1-oxo-2- phenyl-, methyl ester 592z1H-Pyrido[3,4-b]indol-1-one,2-butyl-2,3,4,9-tetrahydro-8-nitro-9-(2-phenylethyl)- 593z9H-Pyrido[3,4-b]indole-9-aceticacid,6-bromo-1,2,3,4-tetrahydro-2-methyl-1-oxo- 594z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2,5,8-trimethyl-9-(phenylmethyl)- 595z9H-Pyrido[3,4-b]indole-9-carboxylicacid,2-[[4-chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorophenyl]methyl]-1,2,3,4-tetrahydro-6-methoxy-1-oxo-,1,1-dimethylethyl ester 596z 1H-Pyrido[3,4-b]indole-1-propanoicacid,2,3,4,9-tetrahydro-3-(methoxycarbonyl)-2-(1-methylethyl)-9-(phenylmethyl)- 597z2-cyclopentyl-N-((R)-2-hydroxy-1-phenylethyl)-2-(4-((2,5,7-trimethyl-1-oxo-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)methyl)phenyl)acetamide 598z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-8-nitro-2-phenyl-9-(2-phenylethyl)- 599z1H-Pyrido[3,4-b]indol-1-one,2-butyl-2,3,4,9-tetrahydro-6-nitro-9-(2-phenylethyl)- 600z9H-Pyrido[3,4-b]indole-9-aceticacid,6-fluoro-1,2,3,4-tetrahydro-2-methyl-1-oxo- 601z1H-Pyrido[3,4-b]indol-1-one,2-butyl-2,3,4,9-tetrahydro-9-(2-phenylethyl)- 602z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-1-oxo-2-phenyl-6-sulfo-, 9- methyl ester 603z9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-6-fluoro-1,2,3,4-tetrahydro-1-oxo- 604z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-6-methyl-1-oxo-2-phenyl-, methyl ester 605z9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-1,2,3,4-tetrahydro-5,8-dimethyl-1-oxo-, methyl ester 606z9H-Pyrido[3,4-b]indole-9-acetic acid, 2-butyl-1,2,3,4-tetrahydro-1-oxo-607z 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2,8-dimethyl-9-(phenylmethyl)- 608z1H-Pyrido[3,4-b]indole-2,9-dicarboxylicacid,1-[3-carboxy-1-(2-carboxyethyl)-1-ethylpropyl]-3,4-dihydro-,2,9-bis(1,1-dimethylethyl) ester 609z9H-Pyrido[3,4-b]indole-9-aceticacid,8-carboxy-1,2,3,4-tetrahydro-1-oxo-2-phenyl-, 9-methyl ester 610z1H-Pyrido[3,4-b]indol-1-one,2-butyl-2,3,4,9-tetrahydro-5,8-dimethyl-9-(2- phenylethyl)- 611z9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-1,2,3,4-tetrahydro-8-methyl-1-oxo-, methyl ester 612z1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-6-methoxy-2-methyl-9-(phenylmethyl)- 613z 1H-Pyrido[3,4-b]indol-1-one,6-bromo-2-butyl-2,3,4,9-tetrahydro-9-(2-phenylethyl)- 614z1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-6-methoxy-2-phenyl-9-(phenylmethyl)- 615z 9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-8-carboxy-1,2,3,4-tetrahydro-1-oxo- 616z9H-Pyrido[3,4-b]indole-9-aceticacid,8-carboxy-1,2,3,4-tetrahydro-1-oxo-2-phenyl- 617z1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-7,8-dimethyl-2-phenyl-9-(phenylmethyl)- 618z 9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-1,2,3,4-tetrahydro-6,8-dimethyl-1-oxo- 619z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2,7,8-trimethyl-9-(2-phenylethyl)- 620z1H-Pyrido[3,4-b]indole-1-aceticacid,9-[(1,1-dimethylethoxy)carbonyl]-2,3,4,9- tetrahydro-2-propyl-,methyl ester 621z 9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-6-methyl-1-oxo-2-phenyl- 622z9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-1,2,3,4-tetrahydro-7,8-dimethyl-1-oxo-, methyl ester 623z9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-1,2,3,4-tetrahydro-7,8-dimethyl-1-oxo- 624z2-(2-butyl-7,8-dimethyl-1-oxo-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)aceticacid 625z 1H-Pyrido[3,4-b]indol-1-one,2-butyl-2,3,4,9-tetrahydro-6,8-dimethyl-9-(2- phenylethyl)- 626z1H-Pyrido[3,4-b]indole-8-carboxylicacid,2,3,4,9-tetrahydro-1-oxo-2-phenyl-9-(2- phenylethyl)- 627z9H-Pyrido[3,4-b]indole-9-aceticacid,6-bromo-1,2,3,4-tetrahydro-2-methyl-1-oxo-, methyl ester 628z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2-methyl-8-nitro-9-(phenylmethyl)- 629z1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-6-methyl-2-phenyl-9-(2-phenylethyl)- 630z 1H-Pyrido[3,4-b]indol-1-one,2-butyl-2,3,4,9-tetrahydro-8-nitro-9-(phenylmethyl)- 631z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-2-methyl-8-nitro-1-oxo-, methyl ester 632z9H-Pyrido[3,4-b]indole-9-aceticacid,2-(2,5-dioxo-1-phenyl-3-pyrrolidinyl)-1,2,3,4- tetrahydro-, ethylester 633z 9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-1,2,3,4-tetrahydro-6-nitro-1-oxo-, methyl ester 634z9-benzyl-2-butyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-8-carboxylicacid 635z 9H-Pyrido[3,4-b]indole-9-aceticacid,6-carboxy-1,2,3,4-tetrahydro-2-methyl-1-oxo-, 9-methyl ester 636z9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-1,2,3,4-tetrahydro-6,8-dimethyl-1-oxo-, methyl ester 637z9H-Pyrido[3,4-b]indole-9-aceticacid,8-fluoro-1,2,3,4-tetrahydro-2-methyl-1-oxo- 638z1H-Pyrido[3,4-b]indol-1-one,8-fluoro-2,3,4,9-tetrahydro-2-methyl-9-(2-phenylethyl)- 639z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-5,8-dimethyl-2-phenyl-9-(2- phenylethyl)- 640z1H-Pyrido[3,4-b]indol-1-one,2-butyl-8-fluoro-2,3,4,9-tetrahydro-9-(2-phenylethyl)- 641z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-6-methoxy-2-methyl-1-oxo- 642z9H-Pyrido[3,4-b]indole-9-carboxylicacid,2-[(2E,4E)-5-(benzoyloxy)-2,4-pentadien-1-yl]-1,2,3,4-tetrahydro-1-(2-hydroxyethyl)-, phenylmethyl ester, (1S)-643z 9H-Pyrido[3,4-b]indole-9-carboxylicacid,1,2,3,4-tetrahydro-6-methoxy-1-oxo-, 1,1- dimethylethyl ester 644z(1R,3S)-benzyl 1-(1-adamantyl)-9-(2-chlorobenzyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate 645z 1H-Pyrido[3,4-b]indol-1-one,6-fluoro-2,3,4,9-tetrahydro-2-phenyl-9-(2-phenylethyl)- 646z1H-Pyrido[3,4-b]indol-1-one,2-butyl-6-fluoro-2,3,4,9-tetrahydro-9-(2-phenylethyl)- 647z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-2,8-dimethyl-1-oxo- 648z9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-1,2,3,4-tetrahydro-6-methoxy-1-oxo-, methyl ester 649z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-8-nitro-1-oxo-2-phenyl-, methyl ester 650z1H-Pyrido[3,4-b]indole-6-sulfonicacid,2,3,4,9-tetrahydro-1-oxo-2-phenyl-9-(2- phenylethyl)- 651z2-methyl-1-oxo-9-phenethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-8-carboxylicacid 652z 9H-Pyrido[3,4-b]indole-9-aceticacid,6-fluoro-1,2,3,4-tetrahydro-1-oxo-2-phenyl-, methyl ester 653z1H-Pyrido[3,4-b]indol-1-one,8-fluoro-2,3,4,9-tetrahydro-2-methyl-9-(phenylmethyl)- 654z1H-Pyrido[3,4-b]indole-2,9-dicarboxylicacid,1-[[(4R)-3-ethyltetrahydro-2-[(4-methoxyphenyl)methoxy]-6-oxo-2H-pyran-4-yl]methyl]-3,4-dihydro-, 9-(1,1-dimethylethyl) 2-(phenylmethyl) ester,(1R)- 655z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-6,8-dimethyl-1-oxo-2- phenyl-, methyl ester 656z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-1-oxo-2-phenyl-6-sulfo- 657z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-2-methyl-1-oxo-6-sulfo- 658z1H-Pyrido[3,4-b]indol-1-one, 6-bromo-2,3,4,9-tetrahydro-2-methyl-9-(phenylmethyl)- 659z 9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-8-methyl-1-oxo-2-phenyl-, methyl ester 660z1H-Pyrido[3,4-b]indol-1-one,6-fluoro-2,3,4,9-tetrahydro-2-phenyl-9-(phenylmethyl)- 661z2-methyl-1-oxo-9-phenethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-sulfonicacid 662z 9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-8-nitro-1-oxo-2-phenyl- 663z9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-6-carboxy-1,2,3,4-tetrahydro-1-oxo- 664z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2-methyl-8-nitro-9-(2-phenylethyl)- 665z1-(benzyloxycarbonyl)-4-((9-((2,2,2-trichloroethoxy)carbonyl)-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-ylsulfonyl)methyl)piperidine-4-carboxylic acid666z 9H-Pyrido[3,4-b]indole-9-acetic acid,1,2,3,4-tetrahydro-1-oxo-2-phenyl-,methyl ester 667z1H-Pyrido[3,4-b]indole-6-carboxylicacid,2,3,4,9-tetrahydro-1-oxo-2-phenyl-9- (phenylmethyl)- 668z9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-1,2,3,4-tetrahydro-8-nitro-1-oxo- 669z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2-methyl-6-nitro-9-(2-phenylethyl)- 670z9H-Pyrido[3,4-b]indole-9-aceticacid,6-fluoro-1,2,3,4-tetrahydro-1-oxo-2-phenyl- 671z1H-Pyrido[3,4-b]indol-1-one, 6-bromo-2,3,4,9-tetrahydro-2-phenyl-9-(2-phenylethyl)- 672z 9H-Pyrido[3,4-b]indole-9-aceticacid,8-carboxy-1,2,3,4-tetrahydro-2-methyl-1-oxo-, 9-methyl ester 673z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2,7,8-trimethyl-9-(phenylmethyl)- 674z1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-6-methyl-2-phenyl-9-(phenylmethyl)- 675z 1H-Pyrido[3,4-b]indol-1-one,2-butyl-2,3,4,9-tetrahydro-6,8-dimethyl-9- (phenylmethyl)- 676z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-2,7,8-trimethyl-1-oxo-, methyl ester 677z(1R,3S)-benzyl2-acetyl-9-benzyl-6-fluoro-1-((1-adamantyl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate 678z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-7,8-dimethyl-1-oxo-2- phenyl- 679z1H-Pyrido[3,4-b]indol-1-one,8-fluoro-2,3,4,9-tetrahydro-2-phenyl-9-(phenylmethyl)- 680z1H-Pyrido[3,4-b]indol-1-one, 2-butyl-2,3,4,9-tetrahydro-5,8-dimethyl-9-(phenylmethyl)- 681z 9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-2,5,8-trimethyl-1-oxo-, methyl ester 682z9H-Pyrido[3,4-b]indole-9-aceticacid,6-carboxy-1,2,3,4-tetrahydro-1-oxo-2-phenyl- 683z9-benzyl-2-butyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylicacid 684z 9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-2,6-dimethyl-1-oxo- 685z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2,8-dimethyl-9-(2-phenylethyl)- 686z1H-Pyrido[3,4-b]indole-6-carboxylicacid,2,3,4,9-tetrahydro-1-oxo-2-phenyl-9-(2- phenylethyl)- 687z1H-Pyrido[3,4-b]indol-1-one,2-butyl-2,3,4,9-tetrahydro-6-methyl-9-(2-phenylethyl)- 688z9H-Pyrido[3,4-b]indole-9-acetic acid, 1,2,3,4-tetrahydro-2-methyl-1-oxo-689z Methanone,phenyl[(1R)-1,2,3,4-tetrahydro-1-methyl-9H-pyrido[3,4-b]indol-9-yl]-690z 9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-2-[4-(1,2,4,5-tetrahydro-2-oxobenz[cd]indol-2a(3H)-yl)butyl]- 691z(S)-2-((S)-4-amino-2-(16-((2S,3S)-1-(2-carbamoyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-3-methyl-1-oxopentan-2-ylamino)-16-oxohexadecanamido)-4-oxobutanamido)-3-phenylpropanoic acid 692z 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-8-methyl-2-phenyl-9-(2- phenylethyl)- 693z1H-Pyrido[3,4-b]indol-1-one,2-butyl-2,3,4,9-tetrahydro-8-methyl-9-(2-phenylethyl)- 694z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-2,8-dimethyl-1-oxo-, methyl ester 695z9H-Pyrido[3,4-b]indole-9-aceticacid,6-bromo-2-butyl-1,2,3,4-tetrahydro-1-oxo-, methyl ester 696z1H-Pyrido[3,4-b]indol-1-one,2-butyl-8-fluoro-2,3,4,9-tetrahydro-9-(phenylmethyl)- 697z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-2,5,8-trimethyl-1-oxo- 698z9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-1,2,3,4-tetrahydro-8-methyl-1-oxo- 699z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-6-nitro-1-oxo-2-phenyl-, methyl ester 700z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-2,6,8-trimethyl-1-oxo- 701z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2-methyl-6-nitro-9-(phenylmethyl)- 702z2-butyl-1-oxo-9-phenethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylicacid 703z 9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-2,7,8-trimethyl-1-oxo- 704z9-benzyl-2-methyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-8-carboxylicacid 705z 1H-Pyrido[3,4-b]indole-8-carboxylicacid,2,3,4,9-tetrahydro-1-oxo-2-phenyl-9- (phenylmethyl)- 706z9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-8-fluoro-1,2,3,4-tetrahydro-1-oxo- 707z9H-Pyrido[3,4-b]indole-9-aceticacid,6-bromo-1,2,3,4-tetrahydro-1-oxo-2-phenyl- 708z9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-6-fluoro-1,2,3,4-tetrahydro-1-oxo-, methyl ester 709z9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-1,2,3,4-tetrahydro-6-nitro-1-oxo- 710z1H-Pyrido[3,4-b]indol-1-one,6-fluoro-2,3,4,9-tetrahydro-2-methyl-9-(2-phenylethyl)- 711z9H-Pyrido[3,4-b]indole-9-aceticacid,8-fluoro-1,2,3,4-tetrahydro-1-oxo-2-phenyl-, methyl ester 712z2-butyl-1-oxo-9-phenethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-sulfonicacid 713z 9H-Pyrido[3,4-b]indole-9-aceticacid,6-bromo-2-butyl-1,2,3,4-tetrahydro-1-oxo- 714z1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-6-methoxy-2-methyl-9-(2-phenylethyl)- 715z2-butyl-1-oxo-9-phenethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-8-carboxylicacid 716z 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-6-methoxy-2-phenyl-9-(2- phenylethyl)- 717z9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-1,2,3,4-tetrahydro-5,8-dimethyl-1-oxo- 718z9-benzyl-2-methyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-sulfonicacid 719z 1H-Pyrido[3,4-b]indol-1-one,6-bromo-2,3,4,9-tetrahydro-2-phenyl-9- (phenylmethyl)- 720z1H-Pyrido[3,4-b]indole-1-aceticacid,9-[(1,1-dimethylethoxy)carbonyl]-2,3,4,9-tetrahydro-6-methoxy-2-[(4-methylphenyl)sulfonyl]-, ethyl ester 721z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-6-nitro-1-oxo-2-phenyl- 722z9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-6-carboxy-1,2,3,4-tetrahydro-1-oxo-, 9- methyl ester 723z9-benzyl-2-butyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-sulfonicacid 724z 9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-2-methyl-1-oxo-6-sulfo-, 9- methyl ester 725z2-butyl-9-(2-methoxy-2-oxoethyl)-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-sulfonic acid 726z 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-6,8-dimethyl-2-phenyl-9-(2- phenylethyl)- 727z9H-Pyrido[3,4-b]indole-9-acetic acid,1,2,3,4-tetrahydro-2-methyl-1-oxo-,methyl ester 728z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2,6-dimethyl-9-(phenylmethyl)- 729z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-6-nitro-2-phenyl-9-(2-phenylethyl)- 730z1H-Pyrido[3,4-b]indol-1-one,2-butyl-2,3,4,9-tetrahydro-8-methyl-9-(phenylmethyl)- 731z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-2,6-dimethyl-1-oxo-, methyl ester 732z9H-Pyrido[3,4-b]indole-9-propanenitrile,2-(2,5-dioxo-1-phenyl-3-pyrrolidinyl)-1,2,3,4-tetrahydro- 733z 9H-Pyrido[3,4-b]indole-9-aceticacid,2-[4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butyl]-1,2,3,4-tetrahydro- 734z 9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-1,2,3,4-tetrahydro-6-methyl-1-oxo-, methyl ester 735z1H-Pyrido[3,4-b]indol-1-one,2-butyl-2,3,4,9-tetrahydro-6-methyl-9-(phenylmethyl)- 736z9H-Pyrido[3,4-b]indole-9-aceticacid,8-fluoro-1,2,3,4-tetrahydro-2-methyl-1-oxo-, methyl ester 737z9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-8-carboxy-1,2,3,4-tetrahydro-1-oxo-, 9- methyl ester 738z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-5,8-dimethyl-1-oxo-2- phenyl-, methyl ester 739z9H-Pyrido[3,4-b]indole-9-aceticacid,6-carboxy-1,2,3,4-tetrahydro-2-methyl-1-oxo- 740z1H-Pyrido[3,4-b]indol-1-one, 6-bromo-2,3,4,9-tetrahydro-2-methyl-9-(2-phenylethyl)- 741z 9H-Pyrido[3,4-b]indole-9-aceticacid,6-carboxy-1,2,3,4-tetrahydro-1-oxo-2-phenyl-, 9-methyl ester 742z1H-Pyrido[3,4-b]indol-1-one,2-butyl-2,3,4,9-tetrahydro-7,8-dimethyl-9-(2- phenylethyl)- 743z9H-Pyrido[3,4-b]indole-9-aceticacid,8-carboxy-1,2,3,4-tetrahydro-2-methyl-1-oxo- 744z9-benzyl-2-methyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylicacid 745z Methanone,(3,4-dichloro-2-hydroxyphenyl)[1,3,4,9-tetrahydro-9-[(4-hydroxyphenyl)methyl]-2H-pyrido[3,4-b]indol-2-yl]- 746z (1R,3S)-3-benzyl2-methyl 9-(2-chlorobenzyl)-1-(1-adamantyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,3(9H)-dicarboxylate 747z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-7,8-dimethyl-2-phenyl-9-(2- phenylethyl)- 748z1H-Pyrido[3,4-b]indole-6-sulfonicacid,2,3,4,9-tetrahydro-1-oxo-2-phenyl-9- (phenylmethyl)- 749z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-2-methyl-6-nitro-1-oxo- 750z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2,6,8-trimethyl-9-(phenylmethyl)- 751z9H-Pyrido[3,4-b]indole-9-aceticacid,6-bromo-1,2,3,4-tetrahydro-1-oxo-2-phenyl-, methyl ester 752z1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-6,8-dimethyl-2-phenyl-9-(phenylmethyl)- 753z 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2,6,8-trimethyl-9-(2-phenylethyl)- 754z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-8-methyl-1-oxo-2-phenyl- 755z9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-1,2,3,4-tetrahydro-8-nitro-1-oxo-, methyl ester 756z9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-1,2,3,4-tetrahydro-6-methoxy-1-oxo- 757z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2,6-dimethyl-9-(2-phenylethyl)- 758z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-6-methoxy-1-oxo-2-phenyl-, methyl ester 759z1H-Pyrido[3,4-b]indol-1-one, 2,3,4,9-tetrahydro-5,8-dimethyl-2-phenyl-9-(phenylmethyl)- 760z 9H-Pyrido[3,4-b]indole-9-aceticacid,2-butyl-1,2,3,4-tetrahydro-6-methyl-1-oxo- 761z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2-methyl-9-(2-phenylethyl)- 762z9H-Pyrido[3,4-b]indole-9-acetic acid, 1,2,3,4-tetrahydro-1-oxo-2-phenyl-763z 1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2-phenyl-9-(2-phenylethyl)- 764z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-2,6,8-trimethyl-1-oxo-, methyl ester 765z9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-5,8-dimethyl-1-oxo-2- phenyl- 766z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-8-nitro-2-phenyl-9-(phenylmethyl)- 767z2-(2-butyl-1-oxo-6-sulfo-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)aceticacid 768z 1H-Pyrido[3,4-b]indole-1-aceticacid,9-[(1,1-dimethylethoxy)carbonyl]-2,3,4,9-tetrahydro-2-[(4-methylphenyl)sulfonyl]-, ethyl ester 769z(1R,3S)-benzyl2-acetyl-9-(4-fluorobenzyl)-1-(1-adamantyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate 770z 9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-6-methoxy-1-oxo-2-phenyl- 771z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-6-nitro-2-phenyl-9-(phenylmethyl)- 772z1H-Pyrido[3,4-b]indol-1-one,2,3,4,9-tetrahydro-2,5,8-trimethyl-9-(2-phenylethyl)- 773z9H-Pyrido[3,4-b]indole-9-aceticacid,8-fluoro-1,2,3,4-tetrahydro-1-oxo-2-phenyl- 774z1H-Pyrido[3,4-b]indol-1-one, 2-butyl-2,3,4,9-tetrahydro-7,8-dimethyl-9-(phenylmethyl)- 775z 9H-Pyrido[3,4-b]indole-9-aceticacid,1,2,3,4-tetrahydro-6-methoxy-2-methyl-1-oxo-, methyl ester 776z1H-Pyrido[3,4-b]indol-1-one,6-fluoro-2,3,4,9-tetrahydro-2-methyl-9-(phenylmethyl)- 777z1H-Pyrido[3,4-b]indol-1-one,8-fluoro-2,3,4,9-tetrahydro-2-phenyl-9-(2-phenylethyl)- 778z1H-Pyrido[3,4-b]indol-1-one,2-butyl-6-fluoro-2,3,4,9-tetrahydro-9-(phenylmethyl)- 779z9H-Pyrido[3,4-b]indole-9-aceticacid,6-fluoro-1,2,3,4-tetrahydro-2-methyl-1-oxo-, methyl ester 780z9H-Pyrido[3,4-b]indole-9-carboxylicacid,2-[(2E,4E)-5-(benzoyloxy)-2,4-pentadien-1-yl]-1,2,3,4-tetrahydro-1-[(2E)-4-methoxy-4-oxo-2-buten-1-yl]-,phenylmethyl ester, (1S)- 781z(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,9-diyl)bis((5-(3-(dihydroxyamino)phenyl)furan-2-yl)methanone) 782z1H-Pyrido[3,4-b]indole,1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-2-[5-[4-(methylsulfonyl)-2-nitrophenyl]-2-pyrimidinyl]-9-[2-(1-pyrrolidinyl)ethyl]-783z 9H-Pyrido[3,4-b]indole-9-ethanamine,1-(1,3-benzodioxol-5-yl)-2-[[5-(4-chloro-2-nitrophenyl)-2-furanyl]carbonyl]-1,2,3,4-tetrahydro-N,N-dimethyl- 784z9H-Pyrido[3,4-b]indole-9-ethanamine,1-(1,3-benzodioxol-5-yl)-2-(benzo[b]thien-2-ylcarbonyl)-1,2,3,4-tetrahydro-N,N-dimethyl- 785z9H-Pyrido[3,4-b]indole-9-ethanamine,1-(1,3-benzodioxol-5-yl)-2-[[5-[2-chloro-5-(trifluoromethyl)phenyl]-2-furanyl]carbonyl]-1,2,3,4-tetrahydro-N,N-dimethyl-786z 9H-Pyrido[3,4-b]indole-9-propanoic acid,1-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-2-[[5-[3-(trifluoromethyl)phenyl]-2-furanyl]carbonyl]-,methyl ester 787z 9H-Pyrido[3,4-b]indole-9-ethanamine,1-(1,3-benzodioxol-5-yl)-2-[[5-(4-chlorophenyl)-2-methyl-3-furanyl]carbonyl]-1,2,3,4-tetrahydro-N,N-dimethyl-788z 1H-Pyrido[3,4-b]indole,1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-9-(2-pyridinylmethyl)-2-[[5-[3-(trifluoromethyl)phenyl]-2-furanyl]carbonyl]-789z 9H-Pyrido[3,4-b]indole-9-ethanamine,1-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-N,N-dimethyl-2-[(5-phenyl-2-furanyl)carbonyl]- 790z1H-Pyrido[3,4-b]indole,1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-9-[2-(1-pyrrolidinyl)ethyl]-2-[[5-[3-(trifluoromethyl)phenyl]-2-furanyl]carbonyl]-791z 9H-Pyrido[3,4-b]indole-9-acetic acid,1-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-2-[[5-(3-nitrophenyl)-2-furanyl]carbonyl]- 792z9H-Pyrido[3,4-b]indole-9-ethanamine,1-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-N,N-dimethyl-2-[5-(2-pyridinyl)-2-pyrimidinyl]- 793z9H-Pyrido[3,4-b]indole-9-ethanamine,1-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-N,N-dimethyl-2-[[5-[3-(trifluoromethyl)phenyl]-2-furanyl]carbonyl]- 794z9H-Pyrido[3,4-b]indole-9-ethanamine,1-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-2-[5-(4-methoxyphenyl)-2-pyrimidinyl]-N,N-dimethyl- 795z9H-Pyrido[3,4-b]indole-9-ethanamine,1-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-N,N-dimethyl-2-[[5-(3-nitrophenyl)-2-furanyl]carbonyl]- 796z9H-Pyrido[3,4-b]indole-9-ethanamine,1-(1,3-benzodioxol-5-yl)-2-(2-benzoxazolyl)-1,2,3,4-tetrahydro-N,N-dimethyl- 797z9H-Pyrido[3,4-b]indole-9-ethanamine,1-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-N,N-dimethyl-2-[[5-(2-nitrophenyl)-2-furanyl]carbonyl]- 798z9H-Pyrido[3,4-b]indole-9-propanamine,1-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-N,N-dimethyl-2-[[5-[3-(trifluoromethyl)phenyl]-2-furanyl]carbonyl]- 799z9H-Pyrido[3,4-b]indole-9-acetic acid,1-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-2-[[5-[3-(trifluoromethyl)phenyl]-2-furanyl]carbonyl]-, methyl ester 800z9H-Pyrido[3,4-b]indole-9-ethanamine,1-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-N,N-dimethyl-2-(1-naphthalenylcarbonyl)- 801z 1H-Pyrido[3,4-b]indole,1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-9-[2-(4-morpholinyl)ethyl]-2-[[5-[3-(trifluoromethyl)phenyl]-2-furanyl]carbonyl]-802z 9H-Pyrido[3,4-b]indole-9-acetic acid,1-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-2-[[5-[3-(trifluoromethyl)phenyl]-2-furanyl]carbonyl]- 803z9H-Pyrido[3,4-b]indole-9-ethanamine,1-(1,3-benzodioxol-5-yl)-2-(2-benzothiazolyl)-1,2,3,4-tetrahydro-N,N-dimethyl- 804z9H-Pyrido[3,4-b]indole-9-ethanamine,1-(1,3-benzodioxol-5-yl)-2-[[5-(1,1-dimethylethyl)-2-furanyl]carbonyl]-1,2,3,4-tetrahydro-N,N-dimethyl- 805z1H-Pyrido[3,4-b]indole-2,9-dicarboxylic acid,3,4-dihydro-1-(1H-indol-3-yl)-, diethyl ester 806z1H-Pyrido[3,4-b]indole,1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-2-[5-(4-methoxyphenyl)-2-pyrimidinyl]-9-[2-(1-pyrrolidinyl)ethyl]- 807z9H-Pyrido[3,4-b]indole-9-ethanamine, 1-(1,3-benzodioxol-5-yl)-2-[[5-(4-chlorophenyl)-2-furanyl]carbonyl]-1,2,3,4-tetrahydro-N,N-dimethyl- 808z9H-Pyrido[3,4-b]indole-9-ethanamine,1-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-N,N-dimethyl-2-[(5-nitro-2-benzofuranyl)carbonyl]- 809z9H-Pyrido[3,4-b]indole-9-ethanamine,1-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-N,N-dimethyl-2-[[5-(4-methyl-2-nitrophenyl)-2-furanyl]carbonyl]- 810z1H-Pyrido[3,4-b]indole,1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-9-(4-pyridinylmethyl)-2-[[5-[3-(trifluoromethyl)phenyl]-2-furanyl]carbonyl]-811z 9H-Pyrido[3,4-b]indole-9-acetic acid,1-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-2-[[5-(3-nitrophenyl)-2-furanyl]carbonyl]-, methyl ester 812z9H-Pyrido[3,4-b]indole-9-ethanamine, 1-(1,3-benzodioxol-5-yl)-2-(2-benzofuranylcarbonyl)-1,2,3,4-tetrahydro-N,N-dimethyl- 813z9H-Pyrido[3,4-b]indole-9-propanoic acid,1-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-2-[[5-[3-(trifluoromethyl)phenyl]-2-furanyl]carbonyl]- 814z9H-Pyrido[3,4-b]indole-9-ethanamine, 1-(1,3-benzodioxol-5-yl)-2-[5-(3,4-dimethoxyphenyl)-2-pyrimidinyl]-1,2,3,4-tetrahydro-N,N-dimethyl- 815z9H-Pyrido[3,4-b]indole-9-ethanamine,1-(1,3-benzodioxol-5-yl)-N,N-diethyl-1,2,3,4-tetrahydro-2-[[5-[3-(trifluoromethyl)phenyl]-2-furanyl]carbonyl]- 816z9H-Pyrido[3,4-b]indole-9-ethanamine, 1-(1,3-benzodioxol-5-yl)-2-[5-(4-chlorophenyl)-2-pyrimidinyl]-1,2,3,4-tetrahydro-N,N-dimethyl- 817z9H-Pyrido[3,4-b]indole-9-ethanamine,1-(1,3-benzodioxol-5-yl)-1,2,3,4-tetrahydro-N,N-dimethyl-2-[[5-(4-nitrophenyl)-2-furanyl]carbonyl]- 818z1H-Pyrido[3,4-b]indole,1-(2,2-difluoro-1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-2,9-bis[[5-(3-nitrophenyl)-2-furanyl]carbonyl]- 819z 1H-Pyrido[3,4-b]indole,1-(2,2-difluoro-1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-2,9-bis[[5-[3-(trifluoromethyl)phenyl]-2-furanyl]carbonyl]-

In one variation, the compound is of the formula (I) wherein R¹ is otherthan a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, an aryloxy or an aralkyl. In one variation the compound isof the formula (I) wherein R⁴ is other than a substituted orunsubstituted aryl.

In another variation, the invention embraces compounds of the formula(I) or any variation herein, including any compound listed in Table 1 ora salt or solvate herein. In a particular variation, the inventionembraces methods of using compounds of the formula (I) or any variationherein, including any compound listed in Table 1 or a salt or solvateherein as detailed herein.

In one variation, the invention embraces a compound of formula (I)wherein at least one of X⁷, X⁸, X⁹ and X¹⁰ is other than CH, providedthat the compound is other than a compound of No. 9x, 10x, 17x, 18x,25x, 32x, 50x, 51x, 58x, 59x, 66x, 83x, 91x, 92x, 99x, 100x, 107x, 124x,131x, 132x, 139x, 140x, 141x, 143x, 148x, 165x, 172x, 174x, 181x, 182x,189x, 197x, 203x, 206x, 212x, 214x, 215x, 222x, 230x, 238x, 244x, 247x,248x, 255x, 256x, 263x, 271x, 279x, 288x, 289x, 290x, 295x, 296x, 297x,304x, 320x, 329x, 330x, 337x, 338x, 345x, 353x, 361x, 362x, 364x, 370x,371x, 377x, 378x, 379x, 386x, 403x, 411x, 418x, 419x, 422x, 427x, 435x,444x, 452x, 453x, 460x, 468x, 485x, 486x, 493x, 494x, 501x, 509x, 526x,527x, 534x, 535x, 542x, 550x, 567x, 568x, 574x, 575x, 576x, 583x, 599x,600x, 608x, 609x, 615x, 616x, 617x, 624x, 640x, 641x, 649x, 650x, 657x,658x, 665x, 667x, 682x, 690x, 691x, 698x, 706x, 722x, 723x, 731x, 732x,739x, 746x, 747x, 755x, 764x, 765x, 770x, 772x, 773x, 780x or 788x inTable 1, or a salt or solvate thereof.

In one variation, the invention embraces a compound of formula (I),provided: (i) when m=q=0, Q is other than phenyl, naphthyl andsubstituted phenyl; and (ii) that the compound is other than a compoundof No. 1x, 2x, 4x, 6x, 11x, 12x, 15x, 16x, 26x, 27x, 30x, 32x, 34x, 35x,42x, 43x, 45x, 46x, 48x, 52x, 53x, 56x, 57x, 67x, 71x, 75x, 76x, 81x,93x, 98x, 101x, 109x, 112x, 116x, 122x, 126x, 129x, 134x, 138x, 139x,142x, 147x, 153x, 157x, 158x, 161x, 166x, 167x, 172x, 175x, 179x, 180x,182x, 201x, 208x, 212x, 213x, 224x, 227x, 229x, 231x, 232x, 235x, 239x,240x, 241x, 242x, 243x, 244x, 249x, 254x, 265x, 268x, 272x, 276x, 279x,280x, 282x, 283x, 284x, 285x, 291x, 295x, 298x, 305x, 306x, 309x, 313x,314x, 320x, 321x, 322x, 323x, 336x, 339x, 346x, 347x, 350x, 353x, 354x,355x, 360x, 361x, 366x, 367x, 369x, 373x, 376x, 377x, 380x, 387x, 388x,391x, 394x, 395x, 399x, 405x, 412x, 413x, 417x, 418x, 420x, 421x, 426x,429x, 432x, 436x, 437x, 438x, 439x, 445x, 446x, 449x, 451x, 459x, 462x,473x, 478x, 480x, 481x, 487x, 492x, 495x, 506x, 510x, 511x, 518x, 519x,521x, 523x, 528x, 529x, 533x, 547x, 552x, 555x, 559x, 562x, 563x, 564x,568x, 569x, 570x, 573x, 574x, 577x, 584x, 588x, 592x, 593x, 599x, 601x,610x, 611x, 614x, 615x, 625x, 626x, 629x, 630x, 631x, 633x, 639x, 640x,645x, 646x, 650x, 651x, 655x, 656x, 659x, 670x, 673x, 674x, 675x, 683x,689x, 696x, 697x, 700x, 708x, 711x, 715x, 719x, 725x, 728x, 730x, 733x,746x, 749x, 752x, 755x, 756x, 757x, 758x, 759x, 762x, 770x, 771x, 782x,785x, 789x or 793x in Table 1, or a salt or solvate thereof.

In one variation, the invention embraces a compound of formula (I),provided: (i) when q=0, CR³R^(3b) is not C═O; and (ii) that the compoundis other than a compound of No. 1x, 2x, 4x, 6x, 7x, 1x, 12x, 13x, 15x,16x, 18x, 21x, 23x, 24x, 26x, 27x, 30x, 35x, 42x, 43x, 45x, 46x, 47x,48x, 52x, 53x, 54x, 56x, 57x, 59x, 65x, 67x, 71x, 74x, 75x, 76x, 81x,84x, 86x, 88x, 93x, 95x, 98x, 100x, 101x, 103x, 105x, 112x, 116x, 117x,122x, 127x, 129x, 133x, 134x, 136x, 138x, 139x, 141x, 142x, 143x, 146x,147x, 149x, 150x, 153x, 156x, 157x, 161x, 163x, 166x, 168x, 171x, 172x,174x, 175x, 177x, 179x, 180x, 182x, 183x, 199x, 201x, 203x, 209x, 213x,215x, 218x, 220x, 221x, 224x, 227x, 229x, 231x, 235x, 239x, 241x, 242x,243x, 244x, 254x, 256x, 259x, 262x, 265x, 268x, 276x, 279x, 282x, 283x,284x, 285x, 286x, 289x, 291x, 292x, 295x, 297x, 298x, 303x, 305x, 306x,309x, 313x, 314x, 320x, 321x, 322x, 323x, 324x, 326x, 333x, 336x, 338x,339x, 341x, 343x, 346x, 347x, 350x, 354x, 355x, 360x, 361x, 364x, 365x,366x, 367x, 369x, 371x, 372x, 373x, 374x, 376x, 377x, 379x, 380x, 387x,391x, 395x, 396x, 399x, 406x, 412x, 413x, 415x, 417x, 418x, 421x, 422x,425x, 426x, 428x, 429x, 432x, 436x, 437x, 439x, 442x, 445x, 447x, 449x,451x, 453x, 456x, 458x, 459x, 462x, 473x, 478x, 480x, 481x, 488x, 492x,494x, 495x, 497x, 498x, 500x, 503x, 506x, 508x, 518x, 519x, 521x, 523x,528x, 529x, 530x, 533x, 535x, 538x, 540x, 547x, 555x, 559x, 562x, 563x,564x, 565x, 568x, 569x, 570x, 571x, 573x, 574x, 576x, 577x, 579x, 582x,584x, 588x, 592x, 593x, 599x, 601x, 603x, 607x, 610x, 611x, 612x, 614x,615x, 617x, 622x, 625x, 626x, 629x, 630x, 631x, 633x, 634x, 639x, 640x,642x, 643x, 644x, 645x, 646x, 648x, 650x, 651x, 653x, 655x, 656x, 658x,659x, 661x, 663x, 670x, 674x, 675x, 683x, 684x, 685x, 688x, 689x, 691x,694x, 696x, 697x, 700x, 702x, 704x, 711x, 715x, 716x, 717x, 719x, 721x,726x, 728x, 730x, 732x, 733x, 735x, 744x, 752x, 756x, 757x, 758x, 759x,761x, 762x, 767x, 771x, 773x, 774x, 776x, 779x, 782x, 785x or 793x inTable 1, or a salt or solvate thereof.

In one variation, the invention embraces a compound of formula (I)wherein at least one of X⁷, X⁸, X⁹ and X¹⁰ is not CH, provided: (i) whenq=0, CR^(3a)R^(3b) is not C═O; and (ii) that the compound is other thana compound of No. 18x, 59x, 100x, 139x, 141x, 143x, 172x, 174x, 182x,203x, 215x, 244x, 256x, 279x, 289x, 295x, 297x, 320x, 338x, 361x, 364x,371x, 377x, 379x, 418x, 422x, 453x, 494x, 535x, 568x, 574x, 576x, 599x,615x, 617x, 640x, 650x, 658x, 691x, 732x or 773x in Table 1, or a saltor solvate thereof.

In one variation, the invention embraces a compound of formula (I),wherein at least one of X⁷, X⁸, X⁹ and X¹⁰ is not CH, provided: (i) whenm=q=0, Q is other than phenyl, naphthyl and substituted phenyl; and (ii)that the compound is other than a compound of No. 32x, 139x, 172x, 182x,212x, 244x, 279x, 295x, 320x, 353x, 361x, 377x, 418x, 568x, 574x, 599x,615x, 640x, 650x, 746x, 755x or 770x in Table 1, or a salt or solvatethereof.

In one variation, the invention embraces a compound of formula (I)wherein at least one of X⁷, X⁸, X⁹ and X¹⁰ is not CH, provided: (i) whenq=0, CR^(3a)R^(3b) is not C═O; (ii) when m=q=0, Q is other than phenyl,naphthyl and substituted phenyl; and (iii) that the compound is otherthan a compound of No. 182x, 244x, 568x, 650x, 139x, 172x, 295x, 377x,418x, 574x, 615x, 279x, 320x, 361x, 599x or 640x in Table 1, or a saltor solvate thereof.

In another variation, the invention embraces a compound of formula (I)wherein at least one of X⁷, X⁸, X⁹ and X¹⁰ is not CH, provided: (i) whenq=0, CR^(3a)R^(3b) is not C═O; and the compound conforms to one ofprovisions (ii) and (iii): (ii) when m=q=0, Q is other than phenyl,naphthyl, substituted phenyl, alkoxy and phenoxy; (iii) whenCR^(8c)R^(8d) is CH₂, Q is other than Me₂N and Et₂N, and R^(10a) andR^(10b) are other than C₃-C₇ alkyl.

In yet another variation, the invention embraces a compound of formula(I) wherein at least one of X⁷, X⁸, X⁹ and X¹⁰ is not CH, provided: (i)when q=0, CR^(3a)R^(3b) is not C═O; and the compound conforms to one ofprovisions (ii)-(iv): (ii) when q, m, R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are taken together to form —CH₂— or C═O, Q is otherthan phenyl, naphthyl, substituted phenyl, alkoxy and phenoxy; (iii)when q, m, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are takentogether to form —CH₂CH₂—, R¹ is other than H; (iv) when q, m, R^(8a),R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are taken together to form—CH₂CH₂CH₂—, Q is other than Me₂N and Et₂N; or a salt or solvatethereof.

In one variation, a compound of the invention is of the formula (I)where: R¹ is a substituted or unsubstituted C₁-C₈ alkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl or substitutedor unsubstituted aryl; each R^(2a) and R^(2b) is independently H,methyl, fluoro or R^(2a) and R^(2b) are taken together to form acarbonyl moiety; each R^(3a) and R^(3b) is independently H or fluoro;and each R^(1a) and R^(10b) is independently H, halo, hydroxyl or methylor

R^(1a) and R^(10b) are taken together to form a carbonyl. This variationof formula (I) is referred to herein as formula “(Ia)”. All variationsreferring to formula (I), where applicable, may apply equally to any offormula (A)-(D) the same as if each and every variation werespecifically and individually listed.

In one variation, the invention embraces a compound of formula (Ia),provided that the compound is other than a compound of No. 6x, 7x, 11x,13x, 18x, 21x, 27x, 30x, 45x, 47x, 48x, 54x, 59x, 71x, 86x, 93x, 95x,100x, 101x, 103x, 112x, 117x, 127x, 133x, 134x, 136x, 141x, 153x, 156x,168x, 174x, 175x, 177x, 182x, 199x, 203x, 209x, 215x, 218x, 220x, 224x,227x, 256x, 259x, 265x, 268x, 276x, 279x, 286x, 292x, 297x, 298x, 306x,309x, 320x, 324x, 333x, 338x, 339x, 341x, 350x, 364x, 365x, 366x, 369x,371x, 374x, 379x, 391x, 396x, 406x, 412x, 413x, 415x, 432x, 442x, 447x,453x, 456x, 462x, 473x, 488x, 494x, 497x, 498x, 506x, 521x, 529x, 530x,535x, 538x, 547x, 565x, 568x, 569x, 571x, 576x, 577x, 579x, 588x, 599x,603x, 610x, 612x, 617x, 626x, 629x, 630x, 634x, 640x, 644x, 645x, 648x,650x, 651x, 653x, 658x, 661x, 670x, 675x, 685x, 688x, 691x, 694x, 721x,726x, 732x, 735x, 744x, 752x, 767x, 773x, 776x, 782x, 785x or 793x inTable 1, or a salt or solvate thereof. In another variation, e.g., inany of the methods detailed herein, the compound may be of formula (Ia),including any suitable compound in Table 1, such as any compound ofTable 1 listed in this paragraph.

In another variation, the invention embraces a compound of formula (Ia),provided: (i) at least one of X⁷, X⁸, X⁹ and X¹⁰ is not CH; and thecompound conforms to one of provisions (ii) and (iii): (ii) when m=q=0,Q is other than phenyl, naphthyl, substituted phenyl, alkoxy andphenoxy; (iii) when q, m, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) andR^(8f) are taken together to form —CH₂CH₂CH₂—, Q is other than Me₂N andEt₂N; or a salt or solvate thereof.

In another variation, the invention embraces compounds of the formula(A):

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R^(2a) and R^(2b)are taken together to form a carbonyl moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy, unsubstituted amino,substituted amino, cycloalkyl, acylamino or acyloxy or R^(3a) and R^(3b)are taken together to form a carbonyl moiety;

m and q are independently 0 or 1;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, C₁-C₈ alkyl or is taken together with the carbon to whichit is attached and a geminal R₈ to form a cycloalkyl moiety or acarbonyl moiety;

each R^(10a) and R^(10b) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl or R^(1a) and R^(10b) aretaken together to form a carbonyl; and

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl, substituted or a unsubstitutedheterocyclyl, unsubstituted amino, substituted amino, alkoxy, aminoacyl,acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino,

provided that the compound is other than a compound in Table 1,

or a salt or solvate thereof.

In one embodiment, a compound is of the formula (A) provided that thecompound is other than a compound in Table 1 or Table 1a.

In another variation, e.g., in any of the methods detailed herein, thecompound may be of formula (A), including any suitable compounds inTable 1. In another variation, e.g., in any of the methods detailedherein, the compound may be of formula (A), including any suitablecompounds in Table 1a.

In one variation, the invention embraces a compound of formula (A)wherein at least one R⁴ is other than H, provided: (i) when q=0,CR^(3a)R^(3b) is not C═O, and the compound conforms to one of provisions(ii) and (iii): (ii) when m=q=0, Q is other than phenyl, naphthyl,substituted phenyl, alkoxy and phenoxy; (iii) when CR^(8c)R^(8d) is CH₂,Q is other than Me₂N and Et₂N, and R^(10a) and R^(10b) are other thanC₃-C₇ alkyl, or a salt or solvate thereof.

In one variation, the invention embraces a compound of formula (A)wherein at least one R⁴ is other than H, provided: (i) when q=0,CR^(3a)R^(3b) is not C═O; and the compound conforms to one of provisions(ii)-(iv): (ii) when q, m, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) andR^(8f) are taken together to form —CH₂— or C═O, Q is other than phenyl,naphthyl, substituted phenyl, alkoxy and phenoxy; (iii) when q, m,R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are taken together toform —CH₂CH₂—, R¹ is other than H; (iv) when q, m, R^(8a), R^(8b),R^(8c), R^(8d), R^(8e) and R^(8f) are taken together to form—CH₂CH₂CH₂—, Q is other than Me₂N and Et₂N; or a salt or solvatethereof.

The invention also embraces compound of the formula (B):

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R^(2a) and R^(2b)are taken together to form a carbonyl moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy, unsubstituted amino,substituted amino, cycloalkyl, acylamino or acyloxy or R^(3a) and R^(3b)are taken together to form a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8c), R^(8d), R^(8e) and R^(8f) is independently H, hydroxyl,C₁-C₈ alkyl or is taken together with the carbon to which it is attachedand a geminal R₈ to form a cycloalkyl moiety or a carbonyl moiety;

each R^(10a) and R^(10b) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl or R^(10a) and R^(10b) aretaken together to form a carbonyl; and

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl, substituted or a unsubstitutedheterocyclyl, amino, substituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy or acylamino,

provided that the compound is other than a compound of No. 2x, 6x, 16x,27x, 32x, 43x, 45x, 57x, 81x, 93x, 98x, 122x, 134x, 139x, 153x, 161x,172x, 212x, 213x, 229x, 235x, 254x, 268x, 276x, 285x, 295x, 309x, 322x,336x, 346x, 347x, 360x, 377x, 387x, 418x, 432x, 451x, 473x, 478x, 492x,495x, 519x, 533x, 555x, 564x, 574x, 577x, 601x, 610x, 615x, 625x, 626x,630x, 639x, 645x, 656x, 670x, 689x, 711x, 730x, 746x, 752x, 755x, 757x,770x, 771x or 793x in Table 1,

or a salt or solvate thereof.

In one embodiment, a compound is of the formula (B) provided that thecompound is other than a compound in Table 1 or Table 1a.

In another variation, e.g., in any of the methods detailed herein, thecompound may be of formula (B), including any suitable compound in Table1, such as any compound of Table 1 listed hereinabove, or a salt orsolvate thereof. In another variation, e.g., in any of the methodsdetailed herein, the compound may be of formula (B), including anysuitable compound in Table 1a, such as any compound of Table 1a listedhereinabove, or a salt or solvate thereof.

In another variation, the compound is of the formula (B) where Q is asubstituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl, or substituted or a unsubstitutedheterocyclyl, or a salt or solvate thereof. In one variation, thecompound is of the formula (B) or any variation thereof detailed herein,where Q is a carbocycle, such as a 5, 6 or 7 membered carbocycle. In onevariation, the compound is of the formula (B) or any variation thereofdetailed herein, where Q is a heterocycle, such as a 5, 6 or 7 memberedcarbocycle.

In another variation, the compound is of the formula (B) where Q is asubstituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, or a salt or solvate thereof. In another variation, thecompound is of the formula (B) where Q is substituted or unsubstitutedheteroaryl, such as a 5, 6 or 7 membered heteroaryl. In one variation,the compound is of the formula (B) where Q is a substituted orunsubstituted aryl, such as a 5, 6 or 7 membered aryl, or a salt orsolvate thereof.

In one variation, the invention embraces a compound of formula (B),provided: (i) at least one of X⁷, X⁸, X⁹ and X¹⁰ is not CH; (ii)CR^(3a)R^(3b) is not C═O or CHOH; and (iii) R^(1a) and R^(10b) are otherthan C₃-C₇ alkyl, or a salt or solvate thereof.

In one variation, the invention embraces a compound of formula (B),provided: (i) at least one of X⁷, X⁸, X⁹ and X¹⁰ is not CH; (ii)CR^(3a)R^(3b) is not C═O; and (iii) R¹ is other than H, or a salt orsolvate thereof.

The invention also embraces compounds of the formula (C):

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R^(2a) and R^(2b)are taken together to form a carbonyl moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy, unsubstituted amino,substituted amino, cycloalkyl, acylamino or acyloxy or R^(3a) and R^(3b)are taken together to form a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, C₁-C₈ alkyl or is taken together with the carbon to whichit is attached and a geminal R₈ to form a cycloalkyl moiety or acarbonyl moiety;

each R^(10a) and R^(10b) is independently H, halo a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl or R^(1a) and R^(10b) aretaken together to form a carbonyl; and

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl, substituted or a unsubstitutedheterocyclyl, amino, substituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy or acylamino;

provided that the compound is other than a compound of No. 1x, 34x, 48x,52x, 101x, 109x, 126x, 158x, 167x, 175x, 180x, 208x, 224x, 232x, 240x,249x, 265x, 272x, 279x, 280x, 298x, 306x, 320x, 339x, 361x, 388x, 394x,405x, 413x, 420x, 429x, 437x, 446x, 459x, 462x, 487x, 510x, 511x, 528x,552x, 569x, 599x, 630x, 640x, 651x, 673x, 697x, 708x, 725x, 749x, 782xor 789x in Table 1,

or a salt or solvate thereof.

In one embodiment, a compound is of the formula (C) provided that thecompound is other than a compound in Table 1 or Table 1a.

In another variation, e.g., in any of the methods detailed herein, thecompound may be of formula (C), including any suitable compound in Table1, such as any compound of Table 1 listed hereinabove, or a salt orsolvate thereof. In another variation, e.g., in any of the methodsdetailed herein, the compound may be of formula (C), including anysuitable compound in Table 1a, such as any compound of Table 1a listedhereinabove, or a salt or solvate thereof.

In another variation, the compound is of the formula (C) where Q is asubstituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl, or substituted or a unsubstitutedheterocyclyl, or a salt or solvate thereof. In one variation, thecompound is of the formula (C) where Q is a carbocycle, such as a 5, 6or 7 membered carbocycle. In another variation, the compound is of theformula (C) where Q is a heterocycle, such as a 5, 6 or 7 memberedheterocycle.

In another variation, the compound is of the formula (C) where Q is asubstituted or unsubstituted aryl, such as a 5, 6 or 7 membered arylgroup. In another variation, the compound is of the formula (C) where Qis a substituted or unsubstituted heteroaryl, such as a 5, 6 or 7membered heteroaryl group.

In one variation, the invention embraces a compound of formula (C)wherein at least one of X⁷, X⁸, X⁹ and X¹⁰ is not CH, provided: whenR^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) each H, Q is otherthan Me₂N and Et₂N, or a salt or solvate thereof.

The invention also embraces compounds of the formula (D):

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R^(2a) and R^(2b)are taken together to form a carbonyl moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy, unsubstituted amino,substituted amino, cycloalkyl, acylamino or acyloxy or R^(3a) and R^(3b)are taken together to form a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl,carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl,carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8e) and R^(8f) is independently H, hydroxyl, C₁-C₈ alkyl or istaken together with the carbon to which it is attached and a geminal R₈to form a cycloalkyl moiety or a carbonyl moiety;

each R^(10a) and R^(10b) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl or R^(1a) and R^(10b) aretaken together to form a carbonyl; and

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl, substituted or a unsubstitutedheterocyclyl, unsubstituted amino, substituted amino, alkoxy, aminoacyl,acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino;

provided that the compound is other than a compound of No. 1x, 4x, 6x,7x, 9x, 10x, 12x, 13x, 15x, 17x, 18x, 21x, 23x, 24x, 25x, 26x, 30x, 35x,42x, 45x, 46x, 47x, 50x, 51x, 53x, 54x, 56x, 58x, 59x, 65x, 66x, 67x,71x, 74x, 75x, 76x, 83x, 84x, 86x, 88x, 91x, 92x, 95x, 99x, 100x, 103x,105x, 107x, 112x, 116x, 117x, 121x, 124x, 127x, 129x, 131x, 132x, 133x,136x, 138x, 140x, 141x, 142x, 143x, 146x, 147x, 148x, 149x, 150x, 153x,156x, 157x, 161x, 162x, 163x, 165x, 166x, 168x, 171x, 174x, 177x, 179x,181x, 182x, 183x, 189x, 191x, 197x, 199x, 201x, 203x, 204x, 206x, 209x,214x, 215x, 218x, 220x, 221x, 222x, 227x, 230x, 231x, 235x, 238x, 239x,241x, 242x, 243x, 244x, 247x, 248x, 250x, 255x, 256x, 259x, 262x, 263x,268x, 270x, 271x, 282x, 283x, 284x, 285x, 286x, 288x, 289x, 290x, 291x,292x, 296x, 297x, 303x, 304x, 305x, 309x, 313x, 314x, 321x, 323x, 324x,326x, 329x, 330x, 333x, 337x, 338x, 341x, 343x, 345x, 350x, 353x, 354x,355x, 362x, 364x, 365x, 366x, 367x, 369x, 370x, 371x, 372x, 373x, 374x,376x, 378x, 379x, 380x, 386x, 391x, 395x, 396x, 399x, 400x, 403x, 406x,410x, 411x, 412x, 415x, 417x, 419x, 421x, 422x, 425x, 426x, 427x, 428x,432x, 435x, 436x, 438x, 439x, 441x, 442x, 444x, 445x, 447x, 449x, 452x,453x, 456x, 458x, 460x, 468x, 470x, 473x, 480x, 481x, 483x, 485x, 486x,488x, 493x, 494x, 497x, 498x, 500x, 501x, 503x, 506x, 508x, 509x, 518x,521x, 523x, 526x, 527x, 529x, 530x, 534x, 535x, 538x, 540x, 542x, 547x,549x, 550x, 559x, 562x, 563x, 564x, 565x, 567x, 568x, 570x, 571x, 573x,575x, 576x, 579x, 582x, 583x, 584x, 588x, 592x, 593x, 600x, 603x, 607x,608x, 609x, 611x, 612x, 614x, 616x, 617x, 622x, 624x, 629x, 631x, 633x,634x, 641x, 642x, 643x, 644x, 645x, 646x, 648x, 649x, 650x, 653x, 655x,657x, 658x, 659x, 661x, 663x, 665x, 667x, 670x, 674x, 675x, 679x, 680x,681x, 682x, 683x, 684x, 685x, 688x, 690x, 691x, 694x, 696x, 698x, 700x,702x, 704x, 706x, 711x, 715x, 716x, 717x, 719x, 720x, 721x, 722x, 723x,726x, 728x, 731x, 732x, 733x, 735x, 738x, 739x, 744x, 747x, 752x, 756x,758x, 759x, 761x, 762x, 764x, 765x, 767x, 772x, 773x, 774x, 776x, 779x,780x, 785x, 788x or 793x in Table 1,

or a salt or solvate thereof.

In one embodiment, a compound is of the formula (D) provided that thecompound is other than a compound in Table 1 or Table 1a.

In another variation, e.g., in any of the methods detailed herein, thecompound may be of formula (D), including any suitable compound in Table1, such as any compound of Table 1 listed hereinabove, or a salt orsolvate thereof. In another variation, e.g., in any of the methodsdetailed herein, the compound may be of formula (D), including anysuitable compound in Table 1a, such as any compound of Table 1a listedhereinabove, or a salt or solvate thereof.

In another variation, the compound is of the formula (D) where Q issubstituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl, or substituted or a unsubstitutedheterocyclyl, or a salt or solvate thereof. In one variation, thecompound is of the formula (D) where Q is a carbocycle or a heterocycle,such as a 5, 6 or 7 membered carbocycle or heterocycle.

In still another variation, the compound is of the formula (D) where Qis substituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl or a salt or solvate thereof.

In one variation, the invention embraces a compound of formula (D)provided: (i) at least one of X⁷, X⁸, X⁹ and X¹⁰ is not CH; and (ii) Qis other than phenyl, naphthyl, substituted phenyl, alkoxy and phenoxy,or a salt or solvate thereof.

In one variation, the compound is of the formula (E):

where:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy or nitro, or R^(2a) andR^(2b) are taken together with the carbon to which they are attached toform a cycloalkyl moiety or a carbonyl moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy, amino, substitutedamino, cycloalkyl, acylamino or acyloxy or R^(3a) and R^(3b) are takentogether with the carbon to which they are attached to form a cycloalkylmoiety or a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

m and q are independently 0 or 1;

n is 1 or 0, provided that n is 0 only when Q is a substitutedheterocycle wherein the substituted heterocycle is a lactam;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independentlyH, hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy,is taken together with the carbon to which it is attached and a geminalR^(8(a-f)) to form a cycloalkyl moiety or a carbonyl moiety, is takentogether with a geminal R^(8(a-f)) to form a methylene or a substitutedmethylene, is taken together with a vicinal R^(8(a-f)) and the carbonatoms to which they are attached to form a substituted or unsubstitutedC₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl orsubstituted or unsubstituted heterocyclyl moiety or is taken togetherwith a vicinal R^(8(a-f)) to form a bond, provided that when anR^(8(a-f)) is taken together with a vicinal R⁸ to form a bond, thegeminal R^(8(a-f)) is other than hydroxyl;

each R^(10a) and R^(10b) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl, cyano or nitro, or R^(1a)and R^(10b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety or a carbonyl moiety;

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or a unsubstituted heterocyclyl,unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl;

provided that the compound is other than a compound listed in Table 1 ora salt or solvate thereof. In another variation the compound is of theformula (E) provided that the compound is other than a compound listedin Table 1 or Table 1A.

In another variation, the compounds of the invention, and methods ofusing the compounds and administering the compounds as detailed herein,encompass any of the compounds of formula (E), including those listed inTable 1 or Table 1A or a salt thereof.

In one embodiment, “alkyl” refers to and includes saturated linear,branched, or cyclic univalent hydrocarbon structures and combinationsthereof provided that when the alkyl is a cyclic alkyl having more thanone ring, all rings are saturated rings. In this embodiment, which maybe applied as a further variation in each instance in which the term“alkyl” (e.g., “substituted alkyl,” “unsubstituted alkyl” and “C₁-C₈alkyl”) is used herein (including but not limited to compounds of theformula E or any variation thereof), a cyclic alkyl having more than onering in which a first ring is fused to a second or subsequent ringcannot have an aryl or heteroaryl group as the second or subsequentring. Particular alkyl groups of this embodiment are those having 1 to20 carbon atoms. More particular alkyl groups of this embodiment arethose having 1 to 8 carbon atoms.

In one embodiment of formula (E) or any variation thereof detailedherein, each R^(3a) and R^(3b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, cycloalkyl or acylamino or R^(3a) and R^(3b)are taken together with the carbon to which they are attached to form acycloalkyl moiety or a carbonyl moiety and each R^(10a) and R^(10b) isindependently H, a substituted or unsubstituted C₁-C₈ alkyl, or R^(10a)and R^(10b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety or a carbonyl moiety.

In one variation, the compound is of the formula (E) where R¹ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thioalkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy. In another variation, the compoundis of the formula (E) where R¹ is substituted or unsubstituted C₁-C₈alkyl or acyl. In a further variation, the compound is of the formula(E) where R¹ is unsubstituted C₁-C₈ alkyl. Where applicable, anyvariation of formula (E) detailed herein may in additional variations befurther defined by the R¹ moieties of this paragraph.

In one variation, the compound is of the formula (E) where q is 0; m andn are each 1; R¹ is methyl; X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ is H;and X⁹ is CR⁴ where R⁴ is Cl. In one such variation, the compound isfurther defined by Q being a substituted aryl or substituted heteroarylor R^(8c), R^(8d), R^(8e) and R^(8f) each being H. In another suchvariation, the compound is further defined by Q being a substituted arylor substituted heteroaryl and R^(8c), R^(8d), R^(8e) and R^(8f) eachbeing H. In a further such variation, Q is a substituted phenyl orsubstituted pyridyl group. When Q is a pyridyl group it may be bound tothe carbon bearing R^(8e) and R^(8f) at any available ring position(e.g., Q can be a 4-pyridyl, 3-pyridyl, 2-pyridyl, etc.). Thesubstituted aryl (e.g., substituted phenyl) or substituted heteroaryl(e.g., substituted pyridyl) in one aspect is substituted with 1 to 5substituents independently selected from halo, cyano, nitro,perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted orunsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino,acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl andaminocarbonylamino moiety. In one such variation, Q is a phenyl orpyridyl substituted with at least one substituted or unsubstitutedC₁-C₈alkyl (e.g., methyl) or halo (e.g., fluoro) moiety. Q may also besubstituted with a single moiety, e.g., 4-fluorophenyl or6-methyl-3-pyridyl. In a particular variation, the compound is of theformula (E) where q is 0; m and n are each 1; R^(8c), R^(8d), R^(8e) andR^(8f) are each H; R¹ is methyl; X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ isH; X⁹ is CR⁴ where R⁴ is Cl; and Q is a phenyl or pyridyl moietysubstituted with a substituted or unsubstituted C₁-C₈alkyl or halogroup.

In another variation, the compound is of the formula (E) where q is 0; mand n are each 1; R^(8c), R^(8d), R^(8e) and R^(8f) are each H; X⁹ isCR⁴ where R⁴ is Cl; and R^(3a) and R^(3b) are each H or substituted orunsubstituted C₁-C₈alkyl. In one such variation, the compound is furtherdefined by Q being a substituted aryl or substituted heteroaryl or R¹being methyl. In another such variation, the compound is further definedby Q being a substituted aryl or substituted heteroaryl and R¹ beingmethyl. When Q is a substituted aryl or substituted heteroaryl, it maybe a moiety as defined in the paragraph immediately above and include aphenyl or pyridyl group substituted with a substituted or unsubstitutedC₁-C₈alkyl (e.g., methyl) or halo (e.g., fluoro) group. In one suchvariation, one of R^(3a) and R^(3b) is substituted or unsubstitutedC₁-C₈alkyl (e.g., a C₁-C₄ alkyl such as methyl or ethyl) and the otheris H. In another such variation, R^(3a) and R^(3b) are both H. In oneaspect, the compound is of the formula (E) where q is 0; m and n areeach 1; R^(8c), R^(8d), R^(8e) and R^(8f) are each H; R¹ is methyl; X⁷,X⁸ and X¹⁰ are each CR⁴ where R⁴ is H; and R^(3a) and R^(3b) are each Hor unsubstituted C₁-C₈alkyl.

In another variation, the compound is of the formula (E) where q is 0; mand n are each 1; R^(8c), R^(8d), R^(8e) and R^(8f) are each H; R¹ ismethyl, at least one of R^(3a) and R^(3b) is substituted orunsubstituted C₁-C₈alkyl and Q is a substituted aryl or substitutedheteroaryl. In one variation, the compound is further defined by X⁹being CR⁴ where R⁴ is halo (e.g., chloro) and/or X⁷, X⁸ and X¹⁰ eachbeing CR⁴ where R⁴ is H. Q may be a substituted aryl or substitutedheteroaryl moiety as detailed in the paragraphs immediately above andinclude a phenyl or pyridyl group substituted with a substituted orunsubstituted C₁-C₈alkyl (e.g., methyl), halo (e.g., fluoro) orperhaloalkyl (e.g., CF₃) group. In one such variation, one of R^(3a) andR^(3b) is substituted or unsubstituted C₁-C₈alkyl (in one variation, oneof R^(3a) and R^(3b) is a C₁-C₄ alkyl such as methyl or ethyl) and theother is H. In another such variation, R^(3a) and R^(3b) are both H. Ina particular variation, the compound is of the formula (E) where q is 0;m and n are each 1; R^(8c), R^(8d), R^(8e) and R^(8f) are each H; R¹ ismethyl, one of R^(3a) and R^(3b) is substituted or unsubstitutedC₁-C₈alkyl and the other is H and Q is a 4-fluorophenyl or6-methyl-3-pyridyl group. In one aspect, the compound is of the formula(E) where q is 0; m and n are each 1; R^(8c), R^(8d), R^(8e) and R^(8f)are each H; R¹ is methyl, R^(3a) and R^(3b) are both H and Q is asubstituted aryl (e.g., a substituted phenyl such as 4-fluorophenyl).

In one variation, the compound is of the formula (E) where q, m and nare each 1; R^(8a), R^(8b)R^(8c), R^(8d), R^(8e) and R^(8f)(collectively “R^(8a-f)”) are each H; X⁹ is CR⁴ where R⁴ is Cl and atleast one of (i)-(iii) applies: (i) R¹ is substituted or unsubstitutedC₁-C₈alkyl; (ii) R^(3a) and R^(3b) are each H; and (iii) Q is asubstituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl. In one variation, the compound is of the formula (E) whereq, m and n are each 1; R^(8a-f) are each H; X⁹ is CR⁴ where R⁴ is Cl andat least two of (i)-(iii) apply. In another variation, the compound isof the formula (E) where q, m and n are each 1; R^(8a-f) are each H; X⁹is CR⁴ where R⁴ is Cl and all of (i)-(iii) apply. In a particularvariation of any of the foregoing in which (iii) applies, Q in oneaspect is an unsubstituted aryl, such as phenyl.

In one variation, the compound is of the formula (E) where q, m and nare each 1; R^(8a-f) are each H; Q is a substituted or unsubstitutedphenyl and R^(3a) and R^(3b) are both H. Q in a particular variation isunsubstituted phenyl. In one aspect, the compound of the foregoingvariations is further defined by X⁹ being CR⁴ where R⁴ is halo (e.g.,chloro).

In another variation, the compound is of the formula (E) where q, m andn are each 1; R^(8a-f) are each H; R¹ is methyl and (i) X⁹ is CR⁴ whereR⁴ is halo or substituted or unsubstituted C₁-C₈alkyl and/or (ii) Q is asubstituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl. In one such variation, X⁹ is CR⁴ where R⁴ is halo. Inanother such variation, Q is unsubstituted aryl. In a particular suchvariation, X⁹ is CR⁴ where R⁴ is halo (e.g., chloro) and Q is anunsubstituted aryl (e.g., phenyl).

In another variation, the compound is of the formula (E) where q is 0; mand n are both 1; R^(3a) and R^(3b) are both H and R¹ is methyl. In onevariation, the compound is further defined by applying one or more of(i)-(iv): (i) X⁹ is CR⁴ where R⁴ is halo (e.g., chloro) or substitutedor unsubstituted C₁-C₈alkyl (e.g., methyl); (ii) R^(8c) and R^(8d) aretaken together to form a carbonyl moiety; (iii) one of R^(8e) and R^(8f)is hydroxyl and the other is H or methyl; and (iv) Q is a substituted orunsubstituted phenyl. In one such variation, (i) and (ii) apply. Inanother variation, (i) and (ii) and (iv) apply. In a further variation,(i) and (iii) apply. In still a further variation, (i), (iii) and (iv)apply.

In another variation, the compound is of the formula (E) where q is 0; mand n are both 1; R¹ is methyl; R^(3a) and R^(3b) are both H and Qcomprises a phenyl or pyridyl moiety. In one such variation, Q is phenylor substituted phenyl. In another such variation, Q is a phenylsubstituted with one halo or one substituted or unsubstituted alkylmoiety. The phenyl may be substituted with one halo moiety such asfluoro or may be substituted with one substituted or unsubstituted alkylmoiety, e.g., a C₁-C₄ alkyl such as methyl. For example, in onevariation, Q may be phenyl, 2-fluorophenyl, 4-fluorophenyl,2-methylphenyl or 4-methylphenyl. In yet another variation, Q is adisubstituted phenyl wherein the phenyl is substituted with at least twomoieties selected from halo and alkoxy. For example, in this variation,Q may be 3,4-difluorophenyl, 3,4-dichlorophenyl,3-fluoro-4-methoxyphenyl. In still another variation, Q is a substitutedpyridyl moiety, such as 6-methyl-3-pyridyl. In a particular variation,the compound is of the formula (E) where q is 0; m and n are both 1; R¹is methyl; R^(3a) and R^(3b) are both H and Q is phenyl, phenylsubstituted with one halo moiety or one alkyl moiety or substitutedpyridyl. In a more particular variation, the compound of any of thethese variations is further defined by one of R^(8c) and R^(8d) beingtaken together with one of R^(8e) and R^(8f) to form a bond and theR^(8c), R^(8d), R^(8e) and R^(8f) that are not taken to form a bond is Hor methyl (thus providing an alkene moiety). In a particular suchvariation, R^(8c) and R^(8d) are taken together with one of R^(8e) andR^(8f) to form a bond and the R^(8c), R^(8d), R^(8e) and R^(8f) that arenot taken to form a bond are H or methyl. In one aspect, the compound isof the formula (E) where q is 0; m and n are both 1; R¹ is methyl;R^(3a) and R^(3b) are both H; one of R^(8c) and R^(8d) being takentogether with one of R^(8e) and R^(8f) to form a bond and the R^(8c) orR^(8d) that is not taken to form a bond is H and the R^(8e) or R^(8f)that is not taken to form a bond is methyl. In a further such variation,the compound is of the formula (E) where q is 0; m and n are both 1; R¹is methyl; R^(3a) and R^(3b) are both H; Q comprises a phenyl or pyridylmoiety; one of R^(8c) and R^(8d) being taken together with one of R^(8e)and R^(8f) to form a bond and the R^(8c) or R^(8d) that is not taken toform a bond is H and the R^(8e) or R^(8f) that is not taken to form abond is methyl.

In another variation, the compound is of the formula (E) where q is 0, mand n are both 1, R^(8c) and R^(8d) are taken together to form acarbonyl and R¹ is methyl. In one such variation the compound is furtherdefined by any one or more of (i)-(iv): (i) R^(8e) and R^(8f) are bothH; (ii) Q is a substituted phenyl; (iii) X⁹ is CR⁴ where R⁴ issubstituted or unsubstituted C₁-C₈alkyl or halo; and (iv) one of R^(3a)and R^(3b) is substituted or unsubstituted C₁-C₈alkyl, phenyl or H andthe other is H. Where more than one (i)-(iv) applies, they may becombined in any manner, e.g., (i) and (ii); (i) and (iv); (ii), (iii)and (iv), (i), (ii), (iii) and (iv), etc. In one variation, Q is aphenyl substituted with a halo group, e.g., 2-fluorophenyl and2-chlorophenyl. In one variation, X⁹ is CR⁴ where R⁴ is methyl orchloro. In a particular variation, the compound is of the formula (E)where q is 0, m and n are both 1, R^(8c) and R^(8d) are taken togetherto form a carbonyl; R¹ is methyl; X⁹ is CR⁴ where R⁴ is methyl orchloro; and Q is a substituted phenyl.

In another variation, the compound is of the formula (E) where q is 0, mand n are each 1 and one of R^(8e) and R^(8f) is hydroxyl. In one suchvariation the compound is further defined by any one or more of(i)-(vii): (i) the R^(8e) or R^(8f) that is not hydroxyl is methyl or H;(ii) R¹ is substituted or unsubstituted C₁-C₈alkyl (which in onevariation is an unsubstituted C₁-C₄ alkyl such as methyl); (iii) X⁹ isCR⁴ where R⁴ is substituted or unsubstituted C₁-C₈alkyl (e.g., methyl)or halo (e.g., chloro); (iv) X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ is H;(v) R^(2a) and R^(2b) are both H; (vi) R^(10a) and R^(10b) are both H;and (vii) Q is a substituted or unsubstituted phenyl or a substituted orunsubstituted pyridyl. In one such variation, (vii) applies and Q is anunsubstituted phenyl or phenyl substituted with a halo or substituted orunsubstituted C₁-C₈alkyl group. Where more than one (i)-(vii) applies,they may be combined in any manner and/or number. For example, in onevariation, all of (i)-(vii) apply and in another, any one or two orthree or more of (i)-(iv) apply. In one variation, (iii) applies and X⁹is CR⁴ where R⁴ is methyl or chloro. In another variation, both (iii)and (vii) apply, and in a particular aspect, X⁹ is CR⁴ where R⁴ ismethyl or chloro and Q is phenyl or 2- or 4-substituted phenyl whereinthe substituent is methyl or fluoro. In a particular variation, thecompound is of the formula (E) where q is 0, m and n are each 1, one ofR^(8e) and R^(8f) is hydroxyl and the other is H or methyl and Q isphenyl or a phenyl substituted with a halo or substituted orunsubstituted alkyl moiety.

In one variation, the compound is of the formula (E) wherein X⁹ is CR⁴where R⁴ is halo or substituted or unsubstituted C₁-C₈alkyl; R¹ ismethyl and at least one of R^(3a) and R^(3b) is ethyl, methyl or phenyl.In one such variation, X⁹ is CR⁴ where R⁴ is chloro or methyl. In oneaspect, the compound is further defined by one or more of (i)-(iv): (i)q is 0; (ii) m and n are each 1; (iii) each R^((8a-f)) is H, whenpresent; (iv) Q is substituted phenyl or substituted pyridyl. Where morethan one (i)-(iv) applies, they may be combined in any manner and/ornumber. For example, in one variation, all of (i)-(iv) apply and inanother, any one or two or three of (i)-(iv) apply. In one variation,all of (i)-(iv) apply and Q is an unsubstituted alkyl-substitutedpyridyl (e.g., 6-methyl-3-pyridyl) or a halo-substituted phenyl (e.g.,4-fluorophenyl). In another variation, the compound is of the formula(E) wherein X⁹ is CR⁴ where R⁴ is halo or substituted or unsubstitutedC₁-C₈alkyl; R¹ is methyl; at least one of R^(3a) and R^(3b) is ethyl,methyl or phenyl and one of R^(8c) and R^(8d) is taken together with oneof R^(8e) and R^(8f) to form a bond and the R^(8c) or R^(8d) that is nottaken to form a bond is H and the R^(8e) or R^(8f) that is not taken toform a bond is substituted or unsubstituted C₁-C₈alkyl (e.g., in onevariation, the moiety is an unsubstituted C₁-C₄ alkyl such as methyl).In this variation, the compound may be further defined by any one ormore of (v)-(vii): (v) one of R^(3a) and R^(3b) is methyl and the otheris H; (vi) X⁹ is CR⁴ where R⁴ is chloro or methyl; and (vii) Q is amono- or di-halo-substituted phenyl (e.g., 2- or 4-fluorophenyl; 2- or4-chlorophenyl; 2,4-di-chlorophenyl; 2,4-difluorophenyl;3,4-dichlorophenyl and 3,4-difluorophenyl). In one such variation, eachof (v)-(vii) applies.

In another variation, the compound is of the formula (E) wherein m and nare both 1 and Q is a substituted phenyl. In one such variation, q isalso 1. In another such variation, q is 0. When Q is a substitutedphenyl, the substituent or substituents may be positioned at anyavailable phenyl ring position. For example, singly- or mono-substitutedphenyl groups may be substituted at the ortho, meta or para-position ofthe phenyl group. Any available phenyl ring substitution pattern issuitable for di- or tri-substituted phenyl groups (e.g., at the orthoand para positions, at two ortho positions, at two meta positions, atthe meta and para positions, at the ortho, meta and para positions, attwo ortho and the para position, at two ortho and a meta position, or attwo meta and a para or ortho position). In one aspect, Q is amono-substituted phenyl wherein the substituent is halo or substitutedor unsubstituted alkyl. In another aspect, Q is a di-substituted phenylwherein both substituents are halo. In a further aspect, Q is adi-substituted phenyl wherein one substituent is halo and the othersubstituent is alkoxy. Q in one variation is a phenyl substituted with 1to 5 moieties where each substituent is independently a halo, cyano,nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl,substituted or unsubstituted heterocyclyl, alkoxy, substituted orunsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl,aminoacyl or aminocarbonylamino moiety. In another variation, Q is aphenyl substituted with at least one substituted or unsubstituted alkyl(e.g., methyl), alkoxy (e.g., methoxy) or halo (e.g., chloro or fluoro)moiety. In still another variation, Q is a phenyl substituted with atleast two halo moieties, which may be the same or different. In anothersuch variation, Q is a phenyl substituted with one halo moiety and onealkoxy moiety. Q in one variation is 2-fluorophenyl, 4-fluorophenyl,4-chlorophenyl, 4-methylphenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl,3,4-dichlorophenyl or 3-fluoro-4-methoxyphenyl. In still another aspect,the compound is according to the foregoing variations wherein thecompound is further defined by any one or more of (i)-(vi): (i) R¹ issubstituted or unsubstituted C₁-C₈alkyl (e.g., methyl); (ii) X⁷, X⁸ andX¹⁰ are each CR⁴ where R⁴ is H; (iii) one of R^(8e) and R^(8f) ishydroxyl and the other is H or methyl; (iv) one of R^(8c) and R^(8d) istaken together with one of R^(8e) and R^(8f) to form a bond and theR^(8c) or R^(8d) that is not taken to form a bond is H and the R^(8e) orR^(8f) that is not taken to form a bond is a substituted orunsubstituted C₁-C₈alkyl (e.g., methyl); (v) q is 0; and (vi) R^(3a) andR^(3b) are independently H, methyl, ethyl or phenyl. Where more than one(i)-(vi) applies, they may be combined in any manner and/or number,provided that provisions (iii) and (iv) are not combined. For example,in one variation, all of (i)-(iii), (v) and (vi) apply and in another,any one or two or three or four or five of (i)-(vi) apply provided that(iii) and (iv) are not combined.

In another variation, the compound is of the formula (E) wherein Q is asubstituted 3-pyridyl (e.g., 6-methyl-3-pyridyl); m and n are each 1 andR^(8c), R^(8d), R^(8e), R^(8f) are each H; R^(10a) and R^(10b) are bothH. In one such variation, the compound is further defined by any one ormore of: (i) R¹ is substituted or unsubstituted C₁-C₈alkyl (e.g.,methyl), (ii) X⁹ is CR⁴ where R⁴ is substituted or unsubstitutedC₁-C₈alkyl (e.g., methyl) or halo (e.g., chloro); (iii) X⁷, X⁸ and X¹⁰are each CR⁴ where R⁴ is H; (iv) R^(1a) and R^(1b) are both H; and (v) qis 0.

In another variation, the compound is of the formula (E) wherein q and mare 0; n is 1 and Q is alkynyl. In a further variation, the compound isof the formula (E) where q and m are 0; n is 1; Q is alkynyl where thealkynyl moiety is acetylenyl. In a further variation, the compound is ofthe formula (E) wherein q and m are 0; n is 1; Q is alkynyl and R¹ issubstituted or unsubstituted C₁-C₈alkyl (e.g., methyl). Such compoundsmay be further defined by one or more of (i)-(v): (i) X⁹ being CR⁴ whereR⁴ is halo (e.g., chloro) or substituted or unsubstituted C₁-C₈alkyl(e.g., methyl); (ii) X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ is H; (iii)R^(2a) and R^(2b) are both H; (iv) R^(10a) and R^(10b) are both H; (v)R^(1a) and R^(3b) are both H. Where more than one (i)-(v) apply, theymay be combined in any manner and/or number. For example, in onevariation, all of (i)-(v) apply and in another, any 1 or any 2 or any 3or any 4 of (i)-(v) apply.

In one such variation, Q is a substituted heterocyclyl wherein thesubstituted heterocyclyl group is a substituted or unsubstituted lactam,q, m and n are each 0 and the compound is of the formula (E-1):

or a salt thereof,

wherein R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b), X⁷, X⁸, X⁹and X¹⁰ are as defined for formula (E).

In certain variations of formula (E-1), Q is of the formula:

In another variation the compound is of the formula (E-1) wherein R¹,R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b), X⁷, X⁸, X⁹ and X¹⁰ areas defined for formula (E) and Q is a substituted or unsubstituted C₃-C₇cycloalkyl, e.g., in one variation Q is

In another variation of formula (E), Q is a phenyl or substitutedphenyl; R¹ is methyl; m and n are both 1; R^(3a) and R^(3b) areindependently H, ethyl, methyl or phenyl and the compound is of theformula (E-2):

wherein q, R^(2a), R^(2b), R^(3a), R^(3b), R^(8a), R^(8b), R^(8c),R^(8d), R^(8e), R^(8f), R^(10a), R^(10b), X⁷, X⁸, X⁹ and X¹⁰ are asdefined for formula (E);

J is halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, acyl, acyloxy,carbonylalkoxy, thioalkyl, substituted or unsubstituted heterocyclyl,alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino,sulfonyl, carbonyl, aminoacyl and aminocarbonylamino moiety; and

T is an integer from 0 to 5.

In another such variation, the compound is of the formula (E-2) and isfurther defined by any one or more of (i)-(viii), provided that only oneof (ii), (iii) and (iv) applies: (i) q is 0; (ii) R^(8c) and R^(8d) areboth H and R^(8e) and R^(8f) are independently H, hydroxyl or methyl;(iii) R^(8c) is taken together with R^(8e) to form a bond and R^(8d) istaken together with R^(8f) to form a bond, such that a triple bondexists between the carbons bearing such R⁸ groups; (iv) one of R^(8c)and R^(8d) is taken together with one of R^(8e) and R^(8f) to form abond and the R^(8c) or R^(8d) that is not taken to form a bond is H andthe R^(8e) or R^(8f) that is not taken to form a bond is H or methyl;(v) X⁹ is CR⁴ where R⁴ is halo (e.g., chloro) or substituted orunsubstituted C₁-C₈alkyl (e.g., methyl); (vi) X⁷, X⁸ and X¹⁰ are eachCR⁴ where R⁴ is H; (vii) R^(2a) and R^(2b) are both H; and (viii)R^(10a) and R^(10b) are both H. Where more than one of (i)-(viii)applies, they may be combined in any manner and/or number, provided thatonly one of (ii), (iii) and (iv) applies. In a particular variation, thecompound is of the formula (E-2), or a variation thereof where any oneor more of (i)-(viii) apply (provided that only one of (ii), (iii) and(iv) applies), where J is halo, perhaloalkyl, alkoxy or a substituted orunsubstituted C₁-C₈ alkyl and T is an integer from 1 to 2.

In another variation, R¹ is methyl; Q is a pyridyl or substitutedpyridyl; R^(3a) and R^(3b) are independently H, ethyl, methyl or phenyland the compound is of the formula (E-3):

wherein q, m, R^(2a), R^(2b), R^(3a), R^(3b), R^(8a)—, R^(8b), R^(8c),R^(8d), R^(8e), R^(8f), R^(10a), R^(10b), X⁷, X⁸, X⁹ and X¹⁰ are asdefined for formula (E);

J is halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, acyl, acyloxy,carbonylalkoxy, thioalkyl, substituted or unsubstituted heterocyclyl,alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino,sulfonyl, carbonyl, aminoacyl and aminocarbonylamino moiety; and

T is an integer from 0 to 4.

In one such variation, the compound is of the formula (E-3) and isfurther defined by any one or more of (i)-(vi): (i) q is 0; (ii) m and qare each 1 and R^(8c), R^(8d), R^(8e) and R^(8f) are each H; (iii) X⁹ isCR⁴ where R⁴ is halo (e.g., chloro) or substituted or unsubstitutedC₁-C₈alkyl (e.g., methyl); (iv) X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ isH; (v) R^(2a) and R^(2b) are both H; and (vi) R^(10a) and R^(10b) areboth H. Where more than one of (i)-(vi) apply, they may be combined inany manner and/or number. The pyridyl ring may be attached to the parentstructure at any available position, e.g., the pyridyl may be a2-pyridyl, 3-pyridyl or 4-pyridyl group. In addition, when T is greaterthan 0, the J substituents may be bound to the pyridyl ring at any ringposition. In one instance, T is 1 and the pyridyl is a 3-pyridyl groupwhere the J moiety is bound at any available ring position. In aparticular variation, the compound is of the formula (E-3), or avariation thereof, including where any one or more of (i)-(vi) apply,where J is substituted or unsubstituted C₁-C₈alkyl and T is an integerfrom 1 to 2. In a particular such variation, J is methyl and T is 1,e.g., to provide a 6-methyl-3-pyridyl.

In another variation, R^(3b) is phenyl, X⁷, X⁸ and X¹⁰ are each CR⁴where R⁴ is H, m and n are each 1 and the compound is of the formula(E-4):

wherein q, m, R^(2a), R^(2b), R^(3a), R^(3b), R^(8a), R^(8b), R^(8c),R^(8d), R^(8e), R^(8f), R^(10a), R^(10b), and X⁹ are as defined forformula (E). In one such variation, the compound is of the formula (E-4)and is further defined by any one or more of (i)-(vi), provided thatprovisions (iv) and (v) are not combined: (i) X⁹ is CR⁴ where R⁴ isother than H (e.g., when R⁴ is substituted or unsubstituted C₁-C₈alkyl);(ii) R¹ is substituted or unsubstituted C₁-C₈ alkyl; (iii) q is 0; (iv)R^(8c) and R^(8d) are taken together to form a carbonyl; (v) one ofR^(8c) and R^(8d) is taken together with one of R^(8e) and R^(8f) toform a bond and the R^(8c) or R^(8d) that is not taken to form a bond isH and the R^(8e) or R^(8f) that is not taken to form a bond issubstituted or unsubstituted C₁-C₈alkyl; and (vi) Q is a substitutedphenyl. Where more than one of (i)-(vi) apply, they may be combined inany manner and/or number provided that (iv) and (v) are not combined.

In another variation, R¹ is methyl, X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴is H, m and n are each 1 and the compound is of the formula (E-5):

wherein:

R^(3a) and R^(3b) are independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy, amino, substitutedamino, cycloalkyl, acylamino, phenyl or acyloxy or R^(3a) and R^(3b) aretaken together with the carbon to which they are attached to form acycloalkyl moiety;

X⁹ is CR⁴ where R⁴ is a substituted or unsubstituted C₁-C₈ alkyl orhalo; and

R^(2a), R^(2b), R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(10a),R^(10b) are as defined for formula (E).

In one such variation, the compound is of the formula (E-5) and isfurther defined by any one or more of (i)-(vi) provided that provisions(iv) and (v) are not combined: (i) X⁹ is CR⁴ where R⁴ is anunsubstituted C₁-C₈ alkyl (e.g., methyl) or halo (e.g., chloro); (ii)R^(3a) and R^(3b) are independently H or unsubstituted C₁-C₈ alkyl;(iii) R^(2a), R^(2b), R^(10a) and R^(10b) are each H; (iv) R^(8c) andR^(8d) are taken together to form a carbonyl; (v) one of R^(8c) andR^(8d) is taken together with one of R^(8e) and R^(8f) to form a bondand the R^(8c) or R^(8d) that is not taken to form a bond is H and theR^(8e) or R^(8f) that is not taken to form a bond is substituted orunsubstituted C₁-C₈alkyl; and (vi) Q is a substituted or unsubstitutedaryl or substituted or unsubstituted heteroaryl. Where more than one of(i)-(vi) apply, they may be combined in any manner and/or numberprovided that (iv) and (v) are not combined.

In one variation, R¹ is methyl, n is 1 and the compound is of theformula (E-6):

wherein:

R^(3a) and R^(3b) are independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy, amino, substitutedamino, cycloalkyl, phenyl, acylamino or acyloxy or R^(3a) and R^(3b) aretaken together with the carbon to which they are attached to form acycloalkyl moiety;

X⁹ is N or CR⁴ where R⁴ is halo or a substituted or unsubstituted C₁-C₈alkyl;

Q comprises a substituted phenyl, unsubstituted phenyl, substitutedpyridyl or unsubstituted pyridyl moiety; and

q, m, X⁷, X⁸, X¹⁰, R^(2a), R^(2b), R^(8a), R^(8b), R^(8c), R^(8d),R^(8e), R^(8f), R^(10a), R^(10b) are as defined for formula (E).

In one such variation, the compound is of the formula (E-6) and isfurther defined by any one or more of (i)-(ix), provided that provisions(iv), (v) and (vi) are not combined in any manner: (i) X⁹ is CR⁴ whereR⁴ is an unsubstituted C₁-C₈ alkyl (e.g., methyl) or halo (e.g.,chloro); (ii) R^(3a) and R^(3b) are independently H, phenyl orunsubstituted C₁-C₈ alkyl; (iii) R^(2a), R^(2b), R^(10a) and R^(10b) areeach H; (iv) m is 1 and R^(8c) and R^(8d) are taken together to form acarbonyl; (v) m is 1 and one of R^(8c) and R^(8d) is taken together withone of R^(8e) and R^(8f) to form a bond and the R^(8c) or R^(8d) that isnot taken to form a bond is H and the R^(8e) or R^(8f) that is not takento form a bond is alkyl or H; (vi) m is 1 and R^(8c) is taken togetherwith R^(8e) to form a bond and R^(8d) is taken together with R^(8f) toform a bond, such that a triple bond is provided; (vii) q is 0; (viii)X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ is H; (ix) Q is a substituted orunsubstituted phenyl or pyridyl moiety. Where more than one of (i)-(ix)apply, they may be combined in any manner and/or number provided thatprovisions (iv), (v) and (vi) are not combined.

In one variation, R¹ is methyl, m and n are both 1 and the compound isof the formula (E-7):

wherein:

R^(3a) and R^(3b) are independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy, amino, substitutedamino, cycloalkyl, phenyl, acylamino or acyloxy or R^(3a) and R^(3b) aretaken together with the carbon to which they are attached to form acycloalkyl moiety;

Q is an unsubstituted cycloalkyl, substituted cycloalkyl, unsubstitutedheterocyclyl or substituted heterocyclyl moiety; and

q, X⁷, X⁸, X⁹, X¹⁰, R^(2a), R^(2b), R^(8a), R^(8b), R^(8c), R^(8d),R^(8e), R^(8f), R^(10a), R^(10b) are as defined for formula (E).

In one such variation, the compound is of the formula (E-7) and isfurther defined by any one or more of (i)-(viii) provided thatprovisions (iv) and (v) are not combined: (i) X⁹ is CR⁴ where R⁴ is H,an unsubstituted C₁-C₈ alkyl (e.g., methyl) or halo (e.g., chloro); (ii)R^(3a) and R^(3b) are each H (iii) R^(2a), R^(2b), R^(10a) and R^(10b)are each H; (iv) R^(8e) and R^(8f) are taken together to form acarbonyl; (v) R^(8c), R^(8d), R^(8e) and R^(8f) are each H; (vi) q is 0;(vii) X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ is H; (viii) Q is asubstituted or unsubstituted cyclopentyl, cyclohexyl, piperidinyl orpiperazinyl moiety. Where more than one of (i)-(viii) apply, they may becombined in any manner and/or number provided that provisions (iv) and(v) are not combined.

In one variation, q is 0, n is 1, R¹ is methyl, R^(3a) and R^(3b) areboth H and the compound is of the formula (E-8):

wherein:

Q is unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl; and

m, n, X⁷, X⁸, X⁹, X¹⁰, R^(2a), R^(2b), R^(8c), R^(8d), R^(8e), R^(8f),R^(10a), R^(10b) are as defined for formula (E). In one such variation,the compound is of the formula (E-8) and is further defined by any oneor more of (i)-(v): (i) R^(2a) and R^(2b) are both H; (ii) R^(10a) andR^(10b) are both H; (iii) R^(8e) and R^(8f) are taken together to form acarbonyl; (iv) X⁹ is CR⁴ where R⁴ is H, halo or unsubstituted C₁-C₈alkyl; and (v) R^(8c) and R^(8d) are both H. Where more than one of(i)-(v) apply, they may be combined in any manner and/or number. In aparticular variation of formula (E-8), R^(8e) and R^(8f) are takentogether to form a carbonyl when Q is unsubstituted amino, substitutedamino or alkoxy.

In one variation, the compound is of the formula (F):

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy or nitro, or R^(2a) andR^(2b) are taken together with the carbon to which they are attached toform a cycloalkyl moiety or a carbonyl moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy, amino, substitutedamino, cycloalkyl, phenyl, acylamino or acyloxy, or R^(3a) and R^(3b)are taken together with the carbon to which they are attached to form acycloalkyl moiety or a carbonyl moiety;

each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;

m and q are independently 0 or 1;

each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c) and R^(8d) is independently H, hydroxyl,C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, is takentogether with the carbon to which it is attached and a geminalR^(8(a-d)) to form a cycloalkyl moiety or a carbonyl moiety, or is takentogether with a geminal R^(8(a-d)) to form a methylene or a substitutedmethylene;

each R^(10a) and R^(10a) is independently H, halo, a substituted orunsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl, cyano or nitro, or R^(10a)and R^(10b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety or a carbonyl moiety;

R¹¹ and R¹² are independently H or C₁-C₈ alkyl, C₁-C₈ perhaloalkyl,carboxy, carbonylalkoxy, or are taken together with the carbon atoms towhich they are attached to form a substituted or unsubstituted C₃₋₈cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl orsubstituted or unsubstituted heterocyclyl moiety or are taken togetherto form a bond, thereby providing an acetylenyl moiety;

indicates the presence of either an E or Z double bond configurationwhen R¹¹ and R¹² are independently H, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl,carboxy or carbonylalkoxy;

Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or a unsubstituted heterocyclyl,unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl.

In one variation, the compound is of the formula (F) where q is 0,

indicates an E double bond configuration, R¹¹ is H and R¹² is C₁-C₈alkyl. In one variation, the compound is of the formula (F) where q is0,

indicates a Z double bond configuration, R¹¹ is H and R¹² is C₁-C₈alkyl.

In one variation, the compound is of the formula (F) where Q is a phenylor substituted phenyl. When Q is a substituted phenyl in one aspect itis substituted with 1 to 5 substituents. When Q is a substituted phenyl,the substituent or substituents may be positioned at any availablephenyl ring position. For example, singly- or mono-substituted phenylgroups may be substituted at the ortho, meta or para-position of thephenyl group. Any available phenyl ring substitution pattern is suitablefor di- or tri-substituted phenyl groups (e.g., at the ortho and parapositions, at two ortho positions, at two meta positions, at the metaand para positions, at the ortho, meta and para positions, at two orthoand the para position, at two ortho and a meta position, or at two metaand a para or ortho position). In one aspect, Q is a mono-substitutedphenyl wherein the substituent is halo (e.g., 2-chlorophenyl,2-fluorophenyl, 4-chlorophenyl and 4-fluorophenyl). In another aspect, Qis a di-substituted phenyl wherein both substituents are halo (e.g.,3,4-difluorophenyl, 3,4-dichlorophenyl and 2,4-dichlorophenyl). In afurther aspect, Q is a di-substituted phenyl wherein one substituent ishalo and the other substituent is alkoxy (e.g.,3-fluoro-4-methoxyphenyl). In one variation, Q is unsubstituted phenyl.In still another aspect, the compound is according to the foregoingvariations is further defined by any one or more of (i)-(xi), providedthat (iv) and (v) are not combined, (ii) and (xi) are not combined and(iii) and (xi) are not combined: (i) q and m are both 0; (ii) R¹¹ is H;(iii) R¹² is an unsubstituted alkyl (e.g., a C₁-C₈ alkyl such asmethyl); (iv) one of R^(3a) and R^(3b) is methyl, ethyl or phenyl andthe other is H; (v) R^(3a) and R^(3b) are both H; (vi) R¹ is alkyl(e.g., a C₁-C₄ alkyl such as methyl); (vii) X⁹ is CR⁴ where R⁴ isunsubstituted alkyl (e.g., methyl) or halo (e.g., chloro); (viii) X⁷, X⁸and X¹⁰ are each CR⁴ where R⁴ is H; (ix) R^(2a) and R^(2b) are both H;(x) R^(1a) and R^(10b) are both H; (xi) R¹¹ and R¹² are taken togetherto form a bond, thereby providing an acetylenyl moiety. Where more thanone (i)-(xi) apply, they may be combined in any manner and/or number,provided that provisions (iv) and (iv) are not combined, provisions (ii)and (xi) are not combined and provisions (iii) and (xi) are notcombined. In a particular variation, provision (iii) applies (R¹² is anunsubstituted alkyl) and the double bond of compound (F) is in the “E”configuration. In another variation, provision (iii) applies (R¹² is anunsubstituted alkyl) and the double bond of compound (F) is in the “Z”configuration.

In a particular variation, the compound is of the formula (F) where Q isunsubstituted phenyl and R¹¹ and R¹² are both H. In a more particularvariation, the compound is further defined by each of provisions (i),(v)-(x): (i) q and m are both 0; (v) R^(3a) and R^(3b) are both H; (vi)R¹ is alkyl (e.g., a C₁-C₄ alkyl such as methyl); (vii) X⁹ is CR⁴ whereR⁴ is unsubstituted alkyl (e.g., methyl) or halo (e.g., chloro); (viii)X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ is H; (ix) R^(2a) and R^(2b) areboth H; and (x) R^(1a) and R^(10b) are both H.

In a particular variation, the compound is of the formula (F) where Q isa substituted phenyl and R¹ and R¹² are both methyl. In a moreparticular variation, the compound is further defined by each ofprovisions (i), (ii), (vii)-(x): (i) q and m are both 0; (ii) R¹¹ is H;(vii) X⁹ is CR⁴ where R⁴ is unsubstituted alkyl (e.g., methyl) or halo(e.g., chloro); (viii) X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ is H; (ix)R^(2a) and R^(2b) are both H; and (x) R^(10a) and R^(1b) are both H. Inan even more particular variation, the compound is of the formula (F)where Q is a substituted phenyl, R¹¹ and R¹² are both methyl, each ofprovisions (i), (ii) and (vii)-(x) apply and provision (iv) alsoapplies: (iv) one of R^(3a) and R^(3b) is methyl, ethyl or phenyl andthe other is H. In still another particular variation, the compound isof the formula (F) where Q is a substituted phenyl, R¹¹ and R¹² are bothmethyl, each of provisions (i), (ii) and (vii)-(x) apply and provision(v) also applies: (v) R^(3a) and R^(3b) are both H.

In one variation of formula (F), q and m are 0, R¹¹ and R¹² areindependently H, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy orcarbonylalkoxy and the compound is of the formula (F-1):

or a salt thereof,

wherein R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b), X⁷, X⁸,X⁹, X¹⁰ and Q are as defined for formula (F).

In one variation, the compound is of the formula (F-1) where

indicates an E double bond configuration, R¹¹ is H and R¹² is C₁-C₈alkyl. In one variation, the compound is of the formula (F-1) where

indicates a Z double bond configuration, R¹¹ is H and R¹² is C₁-C₈alkyl.

In one variation, the compound is of the formula (F-1) wherein Q is asubstituted phenyl group, such as those described for formula (F) above,including but not limited to, mono-substituted phenyl wherein thesubstituent is halo (e.g., 2-chlorophenyl, 2-fluorophenyl,4-chlorophenyl and 4-fluorophenyl) and di-substituted phenyl whereinboth substituents are halo (e.g., 3,4-difluorophenyl, 3,4-dichlorophenyland 2,4-dichlorophenyl) or when one substituent is halo and the other isalkoxy (e.g., 3-fluoro-4-methoxyphenyl). A compound of formula (F-1)where Q is a substituted phenyl may be further defined by any one ormore of (i)-(vi): (i) R¹¹ is H; (ii) R¹² is an unsubstituted alkyl(e.g., a C₁-C₈ alkyl such as methyl); (iii) X⁹ is CR⁴ where R⁴ is halo(e.g., chloro) or alkyl (e.g., methyl); (iv) X⁷, X⁸ and X¹⁰ are each CR⁴where R⁴ is H; (v) R^(2a) and R^(2b) are both H; and (vi) R^(10a) andR^(10b) are both H. Where more than one (i)-(vi) applies, they may becombined in any manner and/or number. In one variation, the compound isof the formula (F-1) where Q is a substituted phenyl and all ofprovisions (i)-(vi) apply.

In a particular variation of formula (F-1), R¹¹ is H and Q is asubstituted or unsubstituted aryl or heteroaryl e.g., a substituted orunsubstituted phenyl or pyridyl. In a more particular variation offormula (F-1), R¹¹ is H, R¹² is H or methyl and Q is a substituted orunsubstituted aryl or heteroaryl. Examples of substituted orunsubstituted phenyl or pyridyl Q groups include, but are not limitedto, 3-pyridyl, 4-pyridyl, 4-methoxyphenyl, 4-chlorophenyl,4-fluorophenyl, 3-fluoro-4-methoxylphenyl, 3,4-dichlorophenyl,3,4-difluorophenyl, 4-methyl-3-pyridyl, 4-fluorophenyl and2-methyl-5-pyrimidyl.

In another variation of formula (F), q and m are 0, R¹¹ and R¹² aretaken together to form a bond and the compound is of the formula (F-2):

or a salt thereof,

wherein R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b), X⁷, X⁸,X⁹, X¹⁰ and Q are as defined for formula (F). In one variation of (F-2),Q is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.

In a particular variation of (F-2), Q is a substituted or unsubstitutedaryl or heteroaryl, e.g., a substituted or unsubstituted phenyl orpyridyl. Examples of Q include, but are not limited to, 4-methoxyphenyl,4-chlorophenyl, 4-fluorophenyl, 3-fluoro-4-methoxyphenyl,3,4-dichlorophenyl, 3,4-difluorophenyl, 3-pyridyl, 4-pyridyl,4-trifluoromethyl-3-pyridyl and 4-methyl-3-pyridyl.

In a further variation of (F-2), Q is a substituted phenyl. In oneaspect, the compound of formula (F-2) where Q is a substituted phenyl,including but not limited to, mono-substituted phenyl wherein thesubstituent is halo (e.g., 2-chlorophenyl, 2-fluorophenyl,4-chlorophenyl and 4-fluorophenyl) and di-substituted phenyl whereinboth substituents are halo (e.g., 3,4-difluorophenyl, 3,4-dichlorophenyland 2,4-dichlorophenyl) or when one substituent is halo and the other isalkoxy (e.g., 3-fluoro-4-methoxyphenyl). The compound of formula (F-2)where Q is a substituted phenyl may be further defined by one or more of(i)-(v): (i) one of R^(3a) and R^(3b) is methyl, ethyl or phenyl and theother is H; (ii) X⁹ is CR⁴ where R⁴ is halo (e.g., chloro) or alkyl(e.g., methyl); (iii) X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ is H; (iv)R^(2a) and R^(2b) are both H; and (v) R^(10a) and R^(10b) are both H.Where more than one (i)-(v) apply, they may be combined in any mannerand/or number. In one variation, the compound is of the formula (F-2)where Q is a substituted phenyl and all of provisions (i)-(v) apply.

In one variation, compounds of the formula (G) are provided:

where R³ is H, methyl, ethyl or phenyl; R⁴ is methyl or chloro; Y is CHor N; R⁹ is fluoro, chloro or methoxy; T is 0, 1 or 2 and each R^(8a),R^(8b), R^(8c) and R^(8d) is independently H, hydroxyl, methyl, is takentogether with the carbon to which it is attached and a geminalR^(8(a-d)) to form a carbonyl moiety or is taken together with a vicinalR^(8(a-d)) to form a bond, or a pharmaceutically acceptable saltthereof. In one embodiment, the compound is of the formula (G) where R³is H. In another embodiment, the compound is of the formula (G) whereeach R^(8a), R^(8b), R^(8c) and R^(8d) is independently H, hydroxyl,methyl. In another embodiment, the compound is of the formula (G) whereR^(8b) is taken together with R^(8d) to form a bond and R^(8a) andR^(8c) are independently H or methyl. In another embodiment, thecompound is of the formula (G) where R³ is H and Y is CH. In anotherembodiment, the compound is of the formula (G) where R³ is H and Y is N.In another embodiment, the compound is of the formula (G) where R³ is H,Y is N and T is 1.

Any formula detailed herein, where applicable, in one variation has eachR^(2a) and R^(2b) independently selected from H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy,unsubstituted amino, substituted amino, cycloalkyl, acylamino or acyloxyor R^(2a) and R^(2b) are taken together to form a cycloalkyl moiety or acarbonyl moiety. It is understood that by “where applicable” it isintended that such R^(2a) and R^(2b) moieties be a variation if theformula encompasses such a structure.

Any formula detailed herein, where applicable, in one variation has eachR^(3a), R^(3b), R^(10a), R^(10b) independently selected from H,hydroxyl, alkoxyl or substituted or unsubstituted C₁-C₈ alkyl. It isunderstood that by “where applicable” it is intended that such R^(3a),R^(3b), R^(10a), R^(10b) moieties be a variation if the formulaencompasses such a structure.

In one variation, compounds of the formula (H-1) are provided:

where R¹ is CH₃; R³ is H, CH₃, ethyl or phenyl; R⁴ is CH₃ or Cl; R^(8c)and R^(8d) are independently H, OH or CH₃; R⁹ is H, F, Cl or OCH₃ and Tis 1 or 2. In one embodiment, the structure is of the formula (H-1)where R³ is H.

In another variation, compounds of the formula (H-2) are provided:

where R¹ is CH₃; R³ is H, CH₃, ethyl or phenyl; R⁴ is CH₃ or Cl; R⁹ isH, F, Cl or OCH₃ and T is 1 or 2. In one embodiment of formula (H-2), R³is H.

In another variation, compounds of the formula (H-3) are provided:

where R¹ is CH₃; R³═H, CH₃, ethyl or phenyl; R⁴ is CH₃ or Cl; R^(8a) andR^(8d) are independently H, OH or CH₃; R⁹ is H, F, Cl or OCH₃ and T is 1or 2. In one embodiment of formula H-3, R³ is H.

In another variation, compounds of the formula (H-4) are provided:

where R¹ is CH₃; R³ is H, CH₃, ethyl or phenyl; R⁴ is CH₃ or Cl; R⁹ isH, F, Cl or OCH₃ and T is 1 or 2. In one embodiment of formula (H-4), R³is H.

In another variation, compounds of the formula (H-5) are provided:

where R¹ is CH₃; R³ is H, CH₃, ethyl or phenyl; R⁴ is CH₃ or Cl; R^(8a)and R^(8c) are independently H, CH₃ or R^(8a) and R^(8c) together form abond; R⁹ is H, F, Cl or OCH₃ and T is 1 or 2. In one embodiment offormula H-5, R³═H.

In another variation, compounds of the formula (H-6) are provided:

where R¹ is CH₃; R³ is H, CH₃, ethyl or phenyl; R⁴ is CH₃ or Cl; R^(8a)and R^(8c) are independently H, CH₃ or R^(8a) and R^(8c) together form abond; R⁹ is H, F, Cl or OCH₃ and T is 1 or 2. In one embodiment offormula H-6, R³ is H.

In a particular embodiment, the compound is of the formula (I), (E), (F)or (Ia) where X⁷, X⁸, X⁹ and X¹⁰ are CR⁴. In another embodiment, thecompound is of the formula (I), (E), (F) or (Ia) where at least one ofX⁷, X⁸, X⁹ and X¹⁰ is N. Another variation provides a compound of theformula (I), (E), (F) or (Ia) where at least two of X⁷, X⁸, X⁹ and X¹⁰are N. A further variation provides a compound of the formula (I), (E),(F) or (Ia) where 2 of X⁷, X⁸, X⁹ and X¹⁰ are N and 2 of X⁷, X⁸, X⁹ andX¹⁰ are CR⁴. A compound of the formula (I), (E), (F) or (Ia) where 1 ofX⁷, X⁸, X⁹ and X¹⁰ is N and 3 of X⁷, X⁸, X⁹ and X¹⁰ are CR⁴ is alsoembraced by this invention.

In another variation, a compound of the invention is of the formula (I),(E), (F) or (Ia) where X⁷, X⁸, X⁹ and X¹⁰ are taken together to providean aromatic moiety selected from the following structures:

where each R⁴ is as defined for formula (I) or (Ia); or in a particularvariation, where each R⁴ is independently hydroxyl, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, alkylsulfonylamino oracyl; or in still a further variation, where R⁴ is independently halo,unsubstituted C₁-C₄ alkyl or C₁-C₄ perhaloalkyl. In another variation,each R⁴ is independently halo or an unsubstituted C₁-C₈ alkyl. In oneembodiment, the foregoing rings are substituted with an (R⁴)₁substituent, such that that aromatic moiety is substituted is a singleR⁴ group, which in one variation is halo or unsubstituted C₁-C₈ alkyl.In one such variation, the foregoing rings have (R⁴)₀ substituents, suchthat that aromatic moiety is unsubstituted and contains no R⁴ groups. Ina further variation, the compound is of the formula (B), (C), (D),(E-1), (E-2), (E-3), (E-6), (E-7), (E-8), (F), (F-1) or (F2) where X⁷,X⁸, X⁹ and X¹⁰ are taken together to provide an aromatic moiety selectedfrom the foregoing structures of this paragraph.

In another variation, a compound of the invention is of the formula (I),(E), (F) or (Ia) where X⁷, X⁸, X⁹ and X¹⁰ are taken together to providean aromatic moiety selected from the following structures:

where each R⁴ is as defined for formula (I) or (la); or in a particularvariation, where each R⁴ is independently alkyl, perhaloalkyl or halo orin an even more particular variation, where each R⁴ is independentlymethyl, trifluoromethyl, chloro or fluoro. In one embodiment, theforegoing rings are substituted with an (R⁴)₁ substituent, such thatthat aromatic moiety is substituted is a single R⁴ group, which in onevariation is halo or unsubstituted C₁-C₈ alkyl. In one such variation,the foregoing rings have (R⁴)₀ substituents, such that that aromaticmoiety is unsubstituted and contains no R⁴ groups. In a furthervariation, the compound is of the formula (B), (C), (D), (E-1), (E-2),(E-3), (E-6), (E-7), (E-8), (F), (F-1) or (F2) where X⁷, X⁸, X⁹ and X¹⁰are taken together to provide an aromatic moiety selected from theforegoing structures of this paragraph.

In a further variation, the compound is of the formula (I), (Ia), (B),(C), (D), (E), (E-1), (E-2), (E-3), (E-6), (E-7), (E-8), (F), (F-1) or(F2) where X⁷, X⁸, X⁹ and X¹⁰ are taken together to provide a structureof the following formulae, where R⁴ may be as defined in any variationhereinabove:

In one such variation, R⁴ is halo or an unsubstituted C₁-C₈ alkyl.

In still a further variation, a compound of the invention is of theformula (I), (E), (F) or (Ia) where X⁷, X⁸, X⁹ and X¹⁰ are takentogether provide an aromatic moiety selected from the followingstructures:

wherein R⁴ is as defined in formula (I); or in a particular variation,where R⁴ is hydroxyl, halo, C₁-C₈ perhaloalkyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,C₁-C₈ alkoxy, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,alkylsulfonylamino or acyl; or in still a further variation, where eachR⁴ is independently halo, unsubstituted C₁-C₄ alkyl or C₁-C₄perhaloalkyl. In another variation, R⁴ is halo or unsubstitutedC₁-C₈alkyl. In still a further variation, the compound is of the formula(B), (C), (D), (E-1), (E-2), (E-3), (E-6), (E-7), (E-8), (F), (F-1) or(F2) where X⁷, X⁸, X⁹ and X¹⁰ are taken together to provide an aromaticmoiety selected from the foregoing structures of this paragraph. In yetanother variation, the compound is of the formula (I), (B), (C), (D),(E), (F), (Ia), (E-1), (E-2), (E-3), (E-6), (E-7), (E-8), (F), (F-1) or(F2) where X⁷, X⁸, X⁹ and X¹⁰ are taken together to provide a structureof the formula:

In still a further variation, a compound of the invention is of theformula (I), (E), (F) or (Ia) where X⁷, X⁸, X⁹ and X¹⁰ are takentogether provide an aromatic moiety selected from the followingstructures:

wherein R⁴ is as defined in formula (I) or in any particular variationherein, such as when each R⁴ is independently alkyl or halo or in aneven more particular variation, where each R⁴ is independently methyl,chloro, iodo or fluoro. In still a further variation, the compound is ofthe formula (B), (C), (D), (E-1), (E-2), (E-3), (E-6), (E-7), (E-8),(F), (F-1) or (F2) where X⁷, X⁸, X⁹ and X¹⁰ are taken together toprovide an aromatic moiety selected from the foregoing structures ofthis paragraph.

In yet another variation, a compound of the invention is of the formula(I), (E), (F) or (Ia) where X⁷, X⁸, X⁹ and X¹⁰ are taken togetherprovide an aromatic moiety selected from the following structures:

In still a further variation, the compound is of the formula (B), (C),(D), (E-1), (E-2), (E-3), (E-6), (E-7), (E-8), (F), (F-1) or (F2) whereX⁷, X⁸, X⁹ and X¹⁰ are taken together to provide an aromatic moietyselected from the foregoing structures of this paragraph.

Any formula detailed herein, where applicable, may in one variation haveX⁷, X⁸, X⁹ and X¹⁰ taken together to provide an aromatic moiety detailedherein above. It is understood that by “where applicable” it is intendedthat in one variation such X⁷, X⁸, X⁹ and X¹⁰ groups are taken togetherto provide a moiety hereinabove if the formula encompasses such astructure. For example, if a given formula does not encompass structureswherein X⁷, X⁸, X⁹ and X¹⁰ groups are taken together provide a pyridylmoiety, then a pyridyl moiety as detailed hereinabove is not applicableto that particular formula, but remains applicable to formulae that doencompass structures where X⁷, X⁸, X⁹ and X¹⁰ groups are taken togetherprovide a pyridyl moiety.

In another embodiment, a compound of the invention is of the formula(I), (E) or (F), wherein X⁷-X¹⁰ are as defined in formula (I) or asdetailed in any variation herein, where R¹ is H, substituted orunsubstituted C₁-C₈ alkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl. In a further embodiment, a compound of the invention is of theformula (I), (E) or (F), wherein X⁷-X¹⁰ are as defined in formula (I) oras detailed in any variation herein, where R¹ is a substituted orunsubstituted C₁-C₈ alkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl or substituted or unsubstituted aryl. In aparticular variation, a compound of the invention is of the formula (I),(E) or (F), wherein X⁷-X¹⁰ are as defined in formula (I) or as detailedin any variation herein, where R¹ is methyl, ethyl, cyclopropyl,propylate, trifluoromethyl, isopropyl, tert-butyl, sec-butyl,2-methylbutyl, propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal,2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl,cyclopentyl, cyclohexyl, substituted phenyl, piperidin-4-yl,hydroxycyclopent-3-yl, hydroxycyclopent-2-yl, hydroxycycloprop-2-yl,1-hydroxy-1-methylcycloprop-2-yl, or1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.

In another variation, the compound of the invention is of the formula(I), (E) or (F), where X⁷-X¹⁰ and R¹ are as defined in formula (I) or asdetailed in any variation herein, where R^(2a) and R^(2b) areindependently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano,nitro or R^(2a) and R^(2b) are taken together to form a carbonyl moietyand each R^(3a) and R^(3b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy,unsubstituted amino, substituted amino, cycloalkyl, acylamino oracyloxy. In another variation, the compound of the invention is of theformula (I), (E) or (F), where X⁷-X¹⁰ and R¹ are as defined in formula(I) or as detailed in any variation herein, where each R^(2a) and R^(2b)is independently H, unsubstituted C₁-C₈ alkyl, halo or R^(2a) and R^(2b)are taken together to form a carbonyl moiety and each R^(3a) and R^(3b)is independently H, unsubstituted C₁-C₈ alkyl, halo or R^(3a) and R^(3b)are taken together to form a carbonyl moiety. In still a furthervariation, the compound of the invention is of the formula (I), (E) or(F), where X⁷-X¹⁰ and R¹ are as defined in formula (I) or as detailed inany variation herein, where each R^(2a) and R^(2b) is independently H,unsubstituted C₁-C₈ alkyl, halo or R^(2a) and R^(2b) are taken togetherto form a carbonyl moiety; and each R^(3a) and R^(3b) is independentlyH, unsubstituted C₁-C₈ alkyl, halo or R^(3a) and R^(3b) are takentogether to form a carbonyl moiety. The invention also embracescompounds of the invention according to formula (I), where X⁷-X¹⁰ and R¹are as defined in formula (I) or as detailed in any variation herein,where each R^(2a) and R^(2b) is independently H, methyl, halo or R^(2a)and R^(2b) are taken together to form a carbonyl moiety and each R^(3a)and R^(3b) is independently H, methyl, halo or R^(3a) and R^(3b) aretaken together to form a carbonyl moiety. The invention further embracescompounds of the invention according to formula (I), where X⁷-X¹⁰ and R¹are as defined in formula (I) or as detailed in any variation herein,where each of R^(2a), R^(2b), R^(3a) and R^(3b) is H. In one variation,a compound of the invention is of the formula (I), (E) or (F) whereX⁷-X¹⁰ and R¹ are as defined in formula (I) or as detailed in anyvariation herein, where at least one of R^(2a), R^(2b), R^(3a) andR^(3b) is a substituted or unsubstituted C₁-C₈ alkyl, halo, cyano, nitroor is taken together with a geminal R² or R³ to form a carbonyl moiety.In another variation, a compound of the invention is of the formula (I),(E) or (F) where X⁷-X¹⁰ and R¹ are as defined in formula (I) or asdetailed in any variation herein, where at least two of R^(2a), R^(2b),R^(3a) and R^(3b) is a substituted or unsubstituted C₁-C₈ alkyl, halo,cyano, nitro or is taken together with a geminal R² or R³ to form acarbonyl moiety. In yet another variation, a compound of the inventionis of the formula (I), (E) or (F) where X⁷-X¹⁰ and R¹ are as defined informula (I) or as detailed in any variation herein, where at least oneof R^(2a), R^(2b), R^(3a) and R^(3b) is fluoro or methyl or is takentogether with a geminal R² or R³ to form a carbonyl moiety. In stillanother variation, a compound of the invention is of the formula (I),(E) or (F) where X⁷-X¹⁰ and R¹ are as defined in formula (I) or asdetailed in any variation herein, where either R^(2a) and R^(2b) orR^(3a) and R^(3b) are each methyl or fluoro (e.g., both R^(2a) andR^(2b) are methyl or one is fluoro and one is methyl) or are takentogether to form a carbonyl moiety. In one variation, R^(2a) and R^(2b)are taken together to form a carbonyl moiety. In another variation, atleast one of R^(2a) and R^(2b) is hydroxyl or alkoxy. In a particularvariation, each R^(2a) and R^(2b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, nitro or R^(2a) and R^(2b) aretaken together to form a carbonyl. In another variation, each R^(2a) andR^(2b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, nitro or R^(2a) and R^(2b) are taken together to form acarbonyl.

The invention also embraces compounds according to formula (I), whereX⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a) and R^(3b) are as defined in formula(I) or as detailed in any variation herein, where each R^(10a) andR^(10b) is independently H, halo, an unsubstituted C₁-C₈ alkyl, hydroxylor R^(10a) and R^(10b) are taken together to form a carbonyl. Alsoembraced are compounds according to formula (I), where X⁷-X¹⁰, R¹,R^(2a), R^(2b), R^(3a) and R^(3b) are as defined in formula (I) or asdetailed in any variation herein, where each R^(10a) and R^(10b) isindependently H, halo, an unsubstituted C₁-C₄ alkyl, hydroxyl or R^(10a)and R^(10b) are taken together to form a carbonyl. In another variation,a compound of the invention is of the formula (I), (E) or (F), whereX⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a) and R^(3b) are as defined in formula(I) or as detailed in any variation herein, where each R^(1a) andR^(10b) is independently H, bromo, methyl, hydroxyl or R^(1a) andR^(10b) are taken together to form a carbonyl. In yet another variation,a compound of the invention is of the formula (I), (E) or (F), whereX⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a) and R^(3b) are as defined in formula(I) or as detailed in any variation herein, where at least one ofR^(10a) and R^(1b) is an unsubstituted C₁-C₈ alkyl, hydroxyl, halo orR^(1a) and R^(1b) are taken together to form a carbonyl. In still afurther variation, a compound of the invention is of the formula (I),(E) or (F), where X⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a) and R^(3b) are asdefined in formula (I) or as detailed in any variation herein, where atleast one of R^(1a) and R^(10b) is methyl, bromo, hydroxyl or R^(10a)and R^(10b) are taken together to form a carbonyl. In another variation,a compound of the invention is of the formula (I), (E) or (F), whereX⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a) and R^(3b) are as defined in formula(I) or as detailed in any variation herein, where both R^(10a) andR^(10b) are methyl. In another variation, a compound of the invention isof the formula (I), (E) or (F), where X⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a)and R^(3b) are as defined in formula (I) or as detailed in any variationherein, where R^(1a) and R^(10b) are taken together to form a carbonyl.In another variation, a compound of the invention is of the formula (I),(E) or (F), where X⁷-X¹⁰, R¹, R^(2a), R^(2b), R^(3a) and R^(3b) are asdefined in formula (I) or as detailed in any variation herein, whereR^(1a) is H and R^(10b) is methyl. In another variation, a compound ofthe invention is of the formula (I), (E) or (F), where X⁷-X¹⁰, R¹,R^(2a), R^(2b), R^(3a) and R^(3b) are as defined in formula (I) or asdetailed in any variation herein, where R^(1a) is H and R^(10b) isbromo. When the carbon of formula (I) bearing R^(1a) and R^(10b) isoptically active, it may be in the S or R configuration and compositionscomprising substantially pure R or S compound or mixtures thereof in anyamount are embraced by this invention.

In a particular variation, a compound of the invention is of the formula(I), (E) or (F) where R^(2a), R^(2b), R¹, R^(10a), R^(10b), R^(3a) andR^(3b) are taken together to form a ring selected from the structures:

where R¹ in the structures above is as defined for formula (I) or anyparticular variation detailed herein. In a particular variation, R¹ ofthe immediately preceding structures is CH₃. In another particularvariation, R¹ of the immediately preceding structures is H. In anothervariation, a compound of the invention is of the formula (I), (E) or (F)where R^(2a), R^(2b), R¹, R^(10a), R^(10b), R^(3a) and R^(3b) are takentogether to form a ring of the structure:

In still another variation, a compound of the invention is of theformula (I), (E) or (F) where R^(2a), R^(2b), R¹, R^(10a), R^(10b),R^(3a) and R^(3b) are taken together to form a ring of the structure:

In a further variation, the compound is of the formula (A), (B), (C),(D), (E-1), (F-1) or (F2) where R^(2a), R^(2b), R¹, R^(10a), R^(10b),R^(3a) and R^(3b) are taken together to provide a moiety selected fromthe foregoing structures of this paragraph. In a further variation andwhere applicable, R¹ is CH₃, the compound is of the formula (E-2),(E-3), (E-5), (E-6), (E-7) or (E-8) where R^(2a), R^(2b), R¹, R^(10a),R^(10b), R^(3a) and R^(3b) are taken together to provide a moietyselected from the foregoing structures of this paragraph. In such avariation, it is understood that where applicable intends that onlystructures conforming to the R^(2a), R^(2b), R¹, R^(10a), R^(10b),R^(3a) and R^(3b) requirements for each formula are embraced (e.g.,where a formula does not allow for R^(3a) and R^(3b) to be combined toform a carbonyl, such structures of this paragraph are not encompassedas a variation for such a structure).

Any formula detailed herein, where applicable, may in one variation haveR^(2a), R^(2b), R¹, R^(10a), R^(10b), R^(3a) and R^(3b) taken togetherto provide a moiety detailed herein above. It is understood that by“where applicable” it is intended that in one variation such R^(2a),R^(2b), R¹, R^(10a), R^(10b), R^(3a) and R^(3b) groups are takentogether to provide a moiety hereinabove if the formula encompasses sucha structure. For example, if a given formula does not encompassstructures wherein R^(2a), R^(2b), R¹, R^(10a), R^(10b), R^(3a) andR^(3b) are taken together provide a

moiety, then a

moiety as detailed hereinabove is not applicable to that particularformula, but remains applicable to formulae that do encompass structureswhere R^(2a), R^(2b), R¹, R^(10a), R^(10b), R^(3a) and R^(3b) are takentogether provide a

moiety.

Compounds of the formulae (IIa), (IIb), (IIc), (IId), (IIe), (IIf),(IIg) and (IIh) are also embraced by this invention:

where in each of (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg) and(IIh), R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b),R^(8a)-R^(8f), m, q and Q are as described for formula (I) or anyapplicable variation thereof. In a particular variation, a compound ofthe invention is of the formula (IIb), (IIc), (IId) or (IIe) and whereR^(2a), R^(2b), R^(10a), R^(10b), R^(3a) and R^(3b) are H and where R¹is an alkyl moiety such as methyl. Where applicable, in each of (IIa),(IIb), (IIc), (IId), (IIe), (IIf), (IIg) and (IIh), R¹, R^(2a), R^(2b),R^(3a), R^(3b), R^(10a), R^(10b), R^(8a)-R^(8f), m, q and Q may also beas described for any formulae or any applicable variation thereofdetailed herein, including but not limited to formulae (A)-(F).

In one embodiment, the invention embraces a compound of any one offormula (IIb), (IIc), (IId), (IIe), (IIf), (IIg) and (IIh) wherein R¹,R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b), R^(8a)-R^(8f), m, qand Q are as described for formula (I) or any applicable variationthereof, or a salt or solvate thereof.

Compounds of the formulae (IIIa), (IIIb), (IIIc), (IIId), (IIIe),(IIIf), (IIIg), (IIIh), (IIIi), (IIIj), (IIIk), (IIIl), (IIIm), (IIIn)and (IIIo) are further embraced this invention:

where in each of (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg),(IIIh), (IIIi), (IIIj), (IIIk), (IIIl), (IIIm), (IIIn) and (IIIo), R¹,R⁴, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b), R^(8a)-R^(8f), m,q and Q are as described for formula (I) or any applicable variationthereof. Where applicable, in each of (IIIa)-(IIIi), R¹, R^(2a), R^(2b),R^(3a), R^(3b), R^(10a), R^(10b), R^(8a)-R^(8f), m, q and Q may also beas described for any formulae or any applicable variation thereofdetailed herein, including but not limited to formulae (A)-(F). In aparticular variation, a compound of the invention is of the formula(IIIa), (IIIb), (IIIc) or (IIId) and where R^(2a), R^(2b), R^(10a),R^(10b), R^(3a) and R^(3b) are H and where R¹ is an alkyl moiety such asmethyl.

In one variation, the invention embraces a compound of formula (IIIa),where R⁴ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl, provided:(i) when q=0, CR^(3a)R^(3b) is not C═O; and the compound conforms to oneof provisions (ii)-(iv): (ii) when q, m, R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are taken together to form —CH₂— or C═O, Q is otherthan phenyl, naphthyl, substituted phenyl, alkoxy and phenoxy; (iii)when q, m, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are takentogether to form —CH₂CH₂—, R^(10a) and R^(10b) are other than C₃-C₇alkyl; (iv) when q, m, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f)are taken together to form —CH₂CH₂CH₂—, Q is other than Me₂N and Et₂N;or a salt or solvate thereof.

In another variation, the invention embraces a compound of formula(IIa), where R⁴ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl, provided:(i) when q=0, CR³R^(3b) is not C═O; and the compound conforms to one ofprovisions (ii)-(iv): (ii) when q, m, R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are taken together to form —CH₂— or C═O, Q is otherthan phenyl, naphthyl, substituted phenyl, alkoxy and phenoxy; (iii)when q, m, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are takentogether to form —CH₂CH₂—, R¹ is other than H; (iv) when q, m, R^(8a),R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are taken together to form—CH₂CH₂CH₂—, Q is other than Me₂N and Et₂N; or a salt or solvatethereof.

In one variation, the invention embraces a compound of formula (IIb),where R⁴ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl, or a saltor solvate thereof.

In one variation, the invention embraces a compound of formula (IIIc),where R⁴ is nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,C₂-C₈ alkoxy, aryloxy, carboxyl, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl, or a saltor solvate thereof.

In one variation, the invention embraces a compound of formula (IIId),where R⁴ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl, or a saltor solvate thereof.

In one variation, the invention embraces a compound of formula (IIIe),provided: (i) at least one R⁴ is other than H; (ii) when q=0,CR^(3a)R^(3b) is not C═O; and the compound conforms to one of provisions(iii) and (iv): (iii) when m=q=0, Q is other than phenyl, naphthyl,substituted phenyl, alkoxy and phenoxy; (iv) when CR^(8c)R^(8d) is CH₂,Q is other than Me₂N and Et₂N, and R^(10a) and R^(10b) are other thanC₃-C₇ alkyl; or a salt or solvate thereof.

In another variation, the invention embraces a compound of formula(IIIe) wherein at least one R⁴ is other than H, provided: (i) when q=0,CR^(3a)R^(3b) is not C═O; and the compound conforms to one of provisions(ii)-(iv): (ii) when q, m, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) andR^(8f) are taken together to form —CH₂— or C═O, Q is other than phenyl,naphthyl, substituted phenyl, alkoxy and phenoxy; (iii) when q, m,R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are taken together toform —CH₂CH₂—, R¹ is other than H; (iv) when q, m, R^(8a), R^(8b),R^(8c), R^(8d), R^(8e) and R^(8f) are taken together to form—CH₂CH₂CH₂—, Q is other than Me₂N and Et₂N; or a salt or solvatethereof.

In one embodiment, the invention embraces a compound of any one offormula (IIIf), (IIIg), (IIIh), (IIIi), (IIIj), (IIIk), (IIIl), (IIIm),(IIIn) and (IIIo) wherein R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a),R^(10b), R^(8a)-R^(8f), m, q and Q are as described for formula (I) orany applicable variation thereof, or a salt or solvate thereof.

Compounds of the formulae (IVa), (IVb), (IVc), (IVd), (IVe), (IVf),(IVg), (IVh), (IVi), (IVj), (IVk), (IVl), (IVm), (IVn), (IVo) and (IVp)are further embraced by this invention:

where in each of (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh),(IVi), (IVj), (IVk), (IVl), (IVm), (IVn), (IVo) and (IVp), R¹, X⁷, X⁸,X⁹, X¹⁰, R^(8a)-R^(8f), m, q and Q are as described for formula (I) orany applicable variation thereof. Where applicable, in each of(IVa)-(IVo), R¹, X⁷, X⁸, X⁹, X¹⁰, R^(8a)-R^(8f), m, q and Q may also beas described for any formulae or any applicable variation thereofdetailed herein, including but not limited to formulae (A)-(F). In aparticular variation, a compound of the invention is of the formula(IVa) and where R¹ is an alkyl moiety such as methyl.

In one variation, the invention embraces a compound of formula (IVa),provided: (i) at least one of X⁷, X⁸, X⁹ and X¹⁰ is not CH; and thecompound conforms to one of provisions (ii) and (iii): (ii) when q, m,R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are taken together toform —CH₂— or C(═O), Q is other than phenyl, naphthyl, substitutedphenyl, alkoxy and phenoxy; (iii) when q, m, R^(8a), R^(8b), R^(8c),R^(8d), R^(8e) and R^(8f) are taken together to form —CH₂CH₂CH₂—, Q isother than Me₂N and Et₂N, or a salt or solvate thereof.

In one variation, the invention embraces a compound of formula (IVd),provided that the compound is other that a compound of No. 81x, 122x,229x, 360x, 451x, 639x or 757x in Table 1, or a salt or solvate thereof.In another variation, e.g., in any of the methods detailed herein, thecompound may be of formula (IVd), including any suitable compound inTable 1, such as any compound of Table 1 listed in this paragraph.

In one variation, the invention embraces a compound of formula (IVd)wherein at least one of X⁷, X⁸, X⁹ and X¹⁰ is not CH, or a salt orsolvate thereof.

In one variation, the invention embraces a compound of formula (IVj),provided that the compound is other that a compound of No. 449x, 540x,643x or 761x in Table 1, or a salt or solvate thereof. In anothervariation, e.g., in any of the methods detailed herein, the compound maybe of formula (IVj), including compound Nos. 449x, 540x, 643x and 761xin Table 1.

In one variation, the invention embraces a compound of formula (IVj)wherein at least one of X⁷, X⁸, X⁹ and X¹⁰ is not CH, or a salt orsolvate thereof. In another variation, the invention embraces a compoundof formula (IVj), provided: when q, m, R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are taken together to form —CH₂— or C(═O), Q is otherthan phenyl, substituted phenyl and alkoxy.

In one variation, the invention embraces a compound of formula (IVl),provided that the compound is other than compound No. 289x in Table 1,or a salt or solvate thereof. In another variation, e.g., in any of themethods detailed herein, the compound may be of formula (IVl), includingcompound No. 289x in Table 1.

In one variation, the invention embraces a compound of formula (IVl),provided: when q, m, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f)are taken together to form —CH₂—, Q is other than substituted phenyl, ora salt or solvate thereof.

In one variation, the invention embraces a compound of formula (IVn),provided: (i) at least one of X⁷, X⁸, X⁹ and X¹⁰ is not CH; and (ii)when q, m, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are takentogether to form —CH₂—, C═O or —CH₂CH₂—, Q is other than phenyl,naphthyl, substituted phenyl and amino, or a salt or solvate thereof.

The invention also embraces compounds of the formulae (Va)-(Vzf):

where in each of (Va)-(Vzf), R¹, R⁴, R^(8a)-R^(8f), m, q and Q are asdescribed for formula (I) or any applicable variation thereof. Whereapplicable, in each of (Va)-(Vzf), R¹, R^(8a)-R^(8f), m, q and Q mayalso be as described for any formulae or any applicable variationthereof detailed herein, including but not limited to formulae (A)-(F).In a particular variation, a compound of the invention is of the formula(Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh) or (vi) and where R⁴ is analkyl moiety such as methyl.

In one variation, the invention embraces a compound of formula (Vf),where R⁴ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl, or a saltor solvate thereof.

In one variation, the invention embraces a compound of formula (Vg),wherein R⁴ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; provided:(i) when q, m, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) aretaken together to form —CH₂— or C═O, Q is other than phenyl, naphthyl,substituted phenyl, alkoxy and phenoxy; or (ii) when q, m, R^(8a),R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are taken together to form—CH₂CH₂CH₂—, Q is other than Me₂N and Et₂N, or a salt or solvatethereof.

In one variation, the invention embraces a compound of formula (Vh),wherein R⁴ is nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,C₁-C₈ alkoxy, aryloxy, carboxyl, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl, or a saltor solvate thereof.

In one variation, the invention embraces a compound of formula (vi),wherein R⁴ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl, or a saltor solvate thereof.

In one variation, the invention embraces a compound of formula (Vm),provided that the compound is other that a compound of No. 81x, 122x,229x, 360x, 451x, 639x or 757x in Table 1, or a salt or solvate thereof.In another variation, e.g., in any of the methods detailed herein, thecompound may be of formula (Vm), including any suitable compound inTable 1, such as any compound of Table 1 listed in this paragraph.

In one variation, the invention embraces a compound of formula (Vm),wherein R⁴ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl, or a saltor solvate thereof.

In one variation, the invention embraces a compound of formula (Vp),provided that the compound is other than compound No. 289x in Table 1,or a salt or solvate thereof. In another variation, e.g., in any of themethods detailed herein, the compound may be of formula (Vp), includingcompound No. 289x in Table 1.

In one variation, the invention embraces a compound of formula (Vp),provided: when q, m, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f)are taken together to form —CH₂—, Q is other than substituted phenyl, ora salt or solvate thereof.

In one variation, the invention embraces a compound of formula (Vr),wherein R⁴ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; provided:when q, m, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are takentogether to form —CH₂—, C═O or —CH₂CH₂—, Q is other than phenyl,naphthyl, substituted phenyl and amino, or a salt or solvate thereof.

In one variation, the invention embraces a compound of formula (Vw),provided that the compound is other that a compound of No. 449x, 540x,643x or 761x in Table 1, or a salt or solvate thereof. In anothervariation, e.g., in any of the methods detailed herein, the compound maybe of formula (Vw), including compound Nos. 449x, 540x, 643x and 761x inTable 1.

In one variation, the invention embraces a compound of formula (Vw),wherein R⁴ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl, or a saltor solvate thereof.

In one variation, the invention embraces a compound of formula (Vx),wherein R⁴ is hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl); provided:(i) when q, m, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) aretaken together to form —CH₂— or C(═O), Q is other than phenyl, naphthyl,substituted phenyl, alkoxy and phenoxy; or (ii) when q, m, R^(8a),R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) are taken together to form—CH₂CH₂CH₂—, Q is other than Me₂N and Et₂N, or a salt or solvatethereof.

In one embodiment, the invention embraces a compound of any one offormula (Vb), (Vc), (Vd), (Ve), (Vy), (Vz), (Vza), (Vzb), (Vzc), (Vzd)and (Vze) wherein R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(10a), R^(10b),R^(8a)-R^(8f), m, q and Q are as described for formula (I) or anyapplicable variation thereof, or a salt or solvate thereof.

In one variation, a compound of the invention is of the formula (I) or(Ia) or any variation of the foregoing detailed herein, or is of any oneof the formulae (IIa)-(IIh), (IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf),where each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) isindependently H, hydroxyl, unsubstituted C₁-C₄ alkyl or is takentogether with the carbon to which it is attached and a geminalR^(8(a-f)) to form a cycloalkyl moiety. In one variation, a compound ofthe invention is of the formula (I) or (Ia) or any variation of theforegoing detailed herein, or is of any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf), where at least one of R^(8a),R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is taken together with thecarbon to which it is attached and a geminal R^(8(a-f)) to form acarbonyl moiety. In another variation, a compound of the invention is ofthe formula (I) or (Ia) or any variation of the foregoing detailedherein, or is of any one of the formulae (IIa)-(IIh), (IIIa)-(IIIo),(IVa)-(IVp) or (Va)-(Vzf), where each R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) is independently H, hydroxyl, methyl or is takentogether with the carbon to which it is attached and a geminalR^(8(a-f)) to form a cyclopropyl moiety. In yet another variation, acompound of the invention is of the formula (I) or (Ia) or any variationof the foregoing detailed herein, or is any one of the formulae(IIa)-(IIh), (IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf), where wherein qis 0 and m is 1. The invention also embraces a compound of the inventionaccording to formula (I) or (Ia) or any variation of the foregoingdetailed herein, or a compound according to any one of the formulae(IIa)-(IIh), (IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf), where q and m areboth 0. The invention further embraces a compound according to formula(I) or (Ia) or any variation of the foregoing detailed herein, or acompound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf), where q, m, R^(8a), R^(8b),R^(8c), R^(8d), R^(8e) and R^(8f) are taken together to form a moietyselected from the group consisting of: —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂—C(H)(OH)—, —C(H)(OH)—CH₂—, —CH₂—C(OH)(CH₃)—, —C(OH)(CH₃)—CH₂—,—CH₂—C(H)(CH₃)—, —C(H)(CH₃)—CH₂—, —CH₂—C(CH₃)(CH₃)—, —C(CH₂CH₂)—CH₂— and—CH₂—C(CH₂CH₂)—.

The invention embraces a compound according to formula (I), (A), (B),(C), (D) or (E) or any variation thereof detailed herein, or a compoundaccording to any one of the formulae (IIa)-(IIh), (IIIa)-(IIIo),(IVa)-(IVp) or (Va)-(Vzf), where each R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) where present, is independently H, hydroxyl, C₁-C₈alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, is taken togetherwith the carbon to which it is attached and a geminal R⁸ to form acycloalkyl moiety or a carbonyl moiety, is taken together with a geminalR⁸ to form a methylene or a substituted methylene, is taken togetherwith a vicinal R⁸ and the carbon atoms to which they are attached toform a substituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl or substituted or unsubstitutedheterocyclyl moiety or is taken together with a vicinal R^(8(a-f)) toform a bond, provided that when an R⁸ is taken together with a vicinalR^(8(a-f)) to form a bond, the geminal R^(8(a-f)) is other thanhydroxyl. In one variation, a compound of the invention is of theformula (I), (A), (B), (C), (D) or (E) or any variation thereof detailedherein, or a compound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf), where each R^(8a), R^(8b),R^(8c), R^(8d), R^(8e) and R^(8f) where present, is independently H,hydroxyl, unsubstituted C₁-C₄ alkyl or is taken together with the carbonto which it is attached and a geminal R⁸ to form a cycloalkyl moiety. Inone variation, a compound of the invention is of the formula (I), (A),(B), (C), (D) or (E) or any variation thereof detailed herein, or acompound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf), where at least one of R^(8a),R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is taken together with thecarbon to which it is attached and a geminal R^(8(a-f)) to form acarbonyl moiety. In another variation, a compound of the invention is ofthe formula (I), (A), (B), (C), (D) or (E) or any variation thereofdetailed herein, or a compound according to any one of the formulae(IIa)-(IIh), (IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf), where eachR^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independently H,hydroxyl, methyl or is taken together with the carbon to which it isattached and a geminal R^(8(a-f)) to form a cyclopropyl moiety. In onevariation, a compound of the invention is of the formula (I), (A), (B),(C), (D) or (E) or any variation thereof detailed herein, or a compoundaccording to any one of the formulae (IIa)-(IIh), (IIIa)-(IIIo),(IVa)-(IVp) or (Va)-(Vzf), where at least one of R^(8a), R^(8b), R^(8c),R^(8d), R^(8e) and R^(8f) is taken together with a geminal R⁸ to form amethylene (CH₂═) or a substituted methylene such as CH₃CH═ or the like.In another variation, a compound of the invention is of the formula (I),(A), (B), (C), (D) or (E) or any variation thereof detailed herein, or acompound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf), where at least one of R^(8ab),R^(8c), R^(8d), R^(8e) and R^(8f) is taken together with a vicinalR^(8(a-f)) to form a bond, where the resultant double bond is in E- orZ-configuration. In one variation, a compound of the invention is of theformula (I), (A), (B), (C), (D) or (E) or any variation thereof detailedherein, or a compound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf), where at least one of R^(8a),R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is taken together with avicinal R^(8(a-f)) and the carbons to which they are attached to form asubstituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl or substituted or unsubstitutedheterocyclyl moiety. In one variation, a compound of the invention is ofthe formula (I), (A), (B), (C), (D) or (E) or any variation thereofdetailed herein, or a compound according to any one of the formulae(IIa)-(IIh), (IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf), where at leastone of R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is takentogether with a vicinal R^(8(a-f)) and the carbons to which they areattached to form a C₃₋₈ cycloalkyl. In one variation, a compound of theinvention is of the formula (I), (A), (B), (C), (D) or (E) or anyvariation thereof detailed herein, or a compound according to any one ofthe formulae (IIa)-(IIh), (IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf),where R^(8c), R^(8d) and the carbon to which they are attached are takentogether with two other R^(8(a-f)) groups that are geminal to each otherand the carbon to which they are attached to form a C₃₋₈ cycloalkenyl.In yet another variation, a compound of the invention is of the formula(I), (A), (B), (C), (D) or (E) or any variation thereof detailed herein,or a compound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf), where wherein q is 0 and mis 1. The invention also embraces a compound of the invention accordingto formula (I), (A), (B), (C), (D) or (E) or any variation thereofdetailed herein, or a compound according to any one of the formulae(IIa)-(IIh), (IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf), where q and m areboth 0.

The invention further embraces a compound according to formula (I), (A),(B), (C), (D) or (E) or any variation thereof detailed herein, or acompound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf), where q, m, R^(8a), R^(8b),R^(8c), R^(8d), R^(8e) and R^(8f) are taken together to form a moietyselected from the group consisting of the structures:

In a further variation and where applicable, a compound of the formulaedetailed herein is provided where q, m, R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) are taken together to form a moiety of the formula:

When the above structures are applied to formula (E) or any variationthereof, it is understood that q, m, n, R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f) where applicable are taken together to form theforegoing moietites, including but not limited to, the structures ofthis paragraph. Likewise, any formula detailed herein, where applicable,may in one variation have q, m, n, R^(8a), R^(8b), R^(8c), R^(8d),R^(8e) and R^(8f), if present, taken together to form a moiety asdetailed herein above, including but not limited to, the structures ofthis paragraph. It is understood that by “where applicable” it isintended that in one variation such q, m, n, R^(8a), R^(8b), R^(8c),R^(8d), R^(8e) and R^(8f) groups, if present, are taken together toprovide a moiety hereinabove if the formula encompasses such astructure. For example, if a given formula does not encompass structureswherein q, m, n, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f)groups, if present, are taken together to provide a —CH₂CH₂-moiety, thena —CH₂CH₂-moiety as detailed hereinabove is not applicable to thatparticular formula, but remains applicable to formulae that do encompassstructures where q, m, n, R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) andR^(8f) groups, if present, are taken together to provide a—CH₂CH₂-moiety.

The invention further embraces a compound according to formula (I), (A),(B), (C), (D) or (E) or any variation thereof detailed herein, or acompound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf), where R^(8c), R^(8d) and thecarbon to which they are attached are taken together with R^(8e), R^(8f)and the carbon to which they are attached or R^(8a), R^(8b) and thecarbon to which they are attached to form a moiety selected from thegroup consisting of the structures, each of which may be optionallysubstituted, where each R⁸ is independently H, hydroxyl, C₁-C₈ alkyl,C₁-C₈ perhaloalkyl, carboxy or carbonylalkoxy:

In another variation, a compound of the invention is of the formula (I),(E), (F) or (Ia) or any variation of the foregoing detailed herein, or acompound according to any one of the formulae (IIIa)-(IIIo), (IVa)-(IVp)or (Va)-(Vzf), where each R⁴ is independently H, halo, substituted orunsubstituted C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, substituted orunsubstituted heterocyclyl or a substituted or unsubstituted aryl. Inyet another variation, a compound of the invention is of the formula(I), (E), (F) or (Ia) or any variation of the foregoing detailed herein,or a compound according to any one of the formulae (IIIa)-(IIIo),(IVa)-(IVp) or (Va)-(Vzf), where each R⁴ is independently H or asubstituted or unsubstituted C₁-C₈ alkyl. In still another variation, acompound of the invention is of the formula (I), (E), (F) or (Ia) or anyvariation of the foregoing detailed herein, or a compound according toany one of the formulae (IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf), whereeach R⁴ is H. The invention also embraces compounds of the formula (I),(E), (F) or (Ia) or any variation of the foregoing detailed herein, or acompound according to any one of the formulae (IIIa)-(IIIo), (IVa)-(IVp)or (Va)-(Vzf), where each R⁴ is independently H, halo, unsubstitutedC₁-C₄ alkyl, C₁-C₄ perhaloalkyl or a substituted or unsubstituted aryl.The invention further embraces compounds of the formula (I), (E), (F) or(Ia) or any variation of the foregoing detailed herein, or a compoundaccording to any one of the formulae (IIIa)-(IIIo), (IVa)-(IVp) or(Va)-(Vzf) where each R⁴ is independently H, halo, methyl,perfluoromethyl or cyclopropyl.

The invention also embraces compounds of the formula (I), (E), (F) or(Ia) or any variation of the foregoing detailed herein, or a compoundaccording to any one of the formulae (IIa)-(IIh), (IIIa)-(IIIo),(IVa)-(IVp) or (Va)-(Vzf) where Q is a substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, which may be but is notlimited to a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl,pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group. In onevariation, a compound of the invention is of the formula (I), (E), (F)or (Ia) or any variation of the foregoing detailed herein, or a compoundaccording to any one of the formulae (IIa)-(IIh), (IIIa)-(IIIo),(IVa)-(IVp) or (Va)-(Vzf) where Q is a substituted or unsubstitutedphenyl or pyridyl group. In a particular variation, Q is a phenyl orpyridyl group substituted with at least one methyl group. In anothervariation, a compound of the invention is of the formula (I), (E), (F)or (Ia) or any variation of the foregoing detailed herein, or a compoundaccording to any one of the formulae (IIa)-(IIh), (IIIa)-(IIIo),(IVa)-(IVp) or (Va)-(Vzf) where Q is a pyridyl, phenyl, pyrimidinyl,pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group substitutedwith at least one substituted or unsubstituted C₁-C₈ alkyl, halo orperhaloalkyl moiety. In still another variation, a compound of theinvention is of the formula (I), (E), (F) or (Ia) or any variation ofthe foregoing detailed herein, or a compound according to any one of theformulae (IIa)-(IIh), (IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf) where Qis a substituted or unsubstituted C₃₋₈ cycloalkyl or a substituted orunsubstituted heterocyclyl. In yet another variation, a compound of theinvention is of the formula (I), (E), (F) or (Ia) or any variation ofthe foregoing detailed herein, or a compound according to any one of theformulae (IIa)-(IIh), (IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf) where Qis a substituted or unsubstituted pyridyl, phenyl, pyrazinyl,piperazinyl, pyrrolidinyl or thiomorpholinyl group. In a particularvariation, Q is a pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinylor thiomorpholinyl group substituted with at least one methyl or halogroup. In one variation, a compound of the invention is of the formula(I), (E), (F) or (Ia) or any variation of the foregoing detailed herein,or a compound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf) where Q is an unsubstitutedC₃₋₈ cycloalkyl or an unsubstituted heterocyclyl. In another variation,a compound of the invention is of the formula (I), (E), (F) or (Ia) orany variation of the foregoing detailed herein, or a compound accordingto any one of the formulae (IIa)-(IIh), (IIIa)-(IIIo), (IVa)-(IVp) or(Va)-(Vzf) where Q is a substituted or unsubstituted cyclohexyl,morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinylmoiety. In yet another variation, a compound of the invention is of theformula (I), (E), (F) or (Ia) or any variation of the foregoing detailedherein, or a compound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf) where Q is a substitutedcyclohexyl, morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl orpyrrolidinyl moiety substituted with at least one carbonyl,hydroxymethyl, methyl or hydroxyl group.

In still another variation, a compound of the invention is of theformula (I), (E), (F) or (Ia) or any variation of the foregoing detailedherein, or a compound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf) where Q is a moiety selectedfrom the structures:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstitutedheterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino,sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. Inone variation, Q is substituted with no more than one R⁹ group. Inanother variation, Q is substituted with only one R⁹ group. In onevariation, Q is substituted with two R⁹ groups. In a further variation,Q is selected from the aromatic structures detailed where the residuehas the moiety (R⁹)₀ such that Q either contains no R⁹ functionality ora moiety of the formula N—R⁹.

In still another variation, a compound of the invention is of theformula (I), (E), (F) or (Ia) or any variation of the foregoing detailedherein, or a compound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf) where Q is a moiety selectedfrom the structures:

wherein each R⁹ is independently alkyl, perhaloalkyl or halo.

In another variation, a compound of the invention is of the formula (I),(E), (F) or (Ia) or any variation of the foregoing detailed herein, or acompound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf) where Q is a moiety selectedfrom the structures:

and wherein R⁹ is connected to Q ortho or para to the position at whichQ is connected to the carbon bearing R^(8e) and R^(8f). In a particularvariation, Q is a structure of the formula:

and R⁹ is connected to Q para to the position at which Q is connected tothe carbon bearing R^(8e) and R^(8f). In another particular variation, Qis a structure of the formula

where each R⁹ is independently alkyl, perhaloalkyl or halo.

In another variation, a compound of the invention is of the formula (I),(E), (F) or (Ia) or any variation of the foregoing detailed herein, or acompound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf) where Q is a moiety selectedfrom the structures:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, alkoxy, substituted orunsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl,aminoacyl or aminocarbonylamino. In one variation, Q is substituted withno more than one R⁹ group. In another variation, Q is substituted withonly one R⁹ group. In yet another variation, Q is substituted with twoR⁹ groups. In a particular variation, Q is selected from the carbocyclicand heterocyclic structures detailed where the residue has the moiety(R⁹)₀ such that Q either contains no R⁹ functionality or a moiety of theformula N—R⁹.

In any structure or variation detailed herein containing an R⁹ group, inone variation, each R⁹ is independently a substituted or unsubstitutedC₁-C₄ alkyl, halo, trifluoromethyl or hydroxyl. In another variation,each R⁹ is independently methyl, —CH₂OH, isopropyl, halo,trifluoromethyl or hydroxyl.

In another variation, a compound of the invention is of the formula (I)or (Ia) or any variation of the foregoing detailed herein, or a compoundaccording to any one of the formulae (IIa)-(IIh), (IIIa)-(IIIo),(IVa)-(IVp) or (Va)-(Vzf) where Q is a moiety selected from thestructures:

In yet another variation, a compound of the invention is of the formula(I) or (Ia) or any variation of the foregoing detailed herein, or acompound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf) where Q is a moiety of thestructure:

In another variation, a compound of the invention is of the formula (I)or (Ia) or any variation of the foregoing detailed herein, or a compoundaccording to any one of the formulae (IIa)-(IIh), (IIIa)-(IIIo),(IVa)-(IVp) or (Va)-(Vzf) where Q is a moiety selected from thestructures:

In yet another variation, a compound of the invention is of the formula(I) or (Ia) or any variation of the foregoing detailed herein, or acompound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf) where Q is a moiety selectedfrom the structures:

In yet another variation, a compound is of any formula detailed hereinand, where applicable, Q is

In yet another variation, a compound of the invention is of the formula(I) or (Ia) or any variation of the foregoing detailed herein, or acompound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf) where Q is a moiety selectedfrom the structures:

In another variation, a compound of the invention is of a formulaedetailed herein, e.g., formula, (I), (A), (B), (C), (D), (E) or (F) orany variation of the foregoing detailed herein, or a compound accordingto any one of the formulae (IIa)-(IIh), (IIIa)-(IIIo), (IVa)-(IVp) or(Va)-(Vzf) where Q is a 6-membered ring heteroaryl or substitutedheteroaryl selected from the structures:

In another variation, a compound of the invention is of a formulaedetailed herein, e.g., formula, (I), (A), (B), (C), (D), (E) or (F) orany variation of the foregoing detailed herein, or a compound accordingto any one of the formulae (IIa)-(IIh), (IIIa)-(IIIo), (IVa)-(IVp) or(Va)-(Vzf) where Q is a phenyl or substituted phenyl selected from thestructures:

In another variation, a compound of the invention is of a formulaedetailed herein, e.g., formula, (I), (A), (B), (C), (D), (E) or (F) orany variation of the foregoing detailed herein, or a compound accordingto any one of the formulae (IIa)-(IIh), (IIIa)-(IIIo), (IVa)-(IVp) or(Va)-(Vzf) where Q is a 5-membered ring heteroaryl or substitutedheteroaryl selected from the structures:

In another variation, a compound of the invention is of a formulaedetailed herein, e.g., formula, (I), (A), (B), (C), (D), (E) or (F) orany variation of the foregoing detailed herein, or a compound accordingto any one of the formulae (IIa)-(IIh), (IIIa)-(IIIo), (IVa)-(IVp) or(Va)-(Vzf) where Q is a 5-membered ring substituted or unsubstitutedcycloalkyl or heterocyclyl selected from the structures:

In another variation, a compound of the invention is of a formulaedetailed herein, e.g., formula, (I), (A), (B), (C), (D), (E) or (F) orany variation of the foregoing detailed herein, or a compound accordingto any one of the formulae (IIa)-(IIh), (IIIa)-(IIIo), (IVa)-(IVp) or(Va)-(Vzf) where Q is a 6-membered ring substituted or unsubstitutedcycloalkyl or heterocyclyl selected from the structures:

In another variation, a compound of the invention is of the formula (I)or (Ia) or any variation of the foregoing detailed herein, or a compoundaccording to any one of the formulae (IIa)-(IIh), (IIIa)-(IIIo),(IVa)-(IVp) or (Va)-(Vzf) where Q is an unsubstituted amino, substitutedamino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxyor acylamino moiety. In a particular variation, Q is an unsubstitutedamino. In another variation, Q is substituted amino of the formula—N(C₁-C₈alkyl)₂ such as the moiety —N(Me)₂-N(CH₃)(CH₂CH₃). In anothervariation, Q is a substituted amino of the formula —N(H)(cycloalkyl orsubstituted cycloalkyl), such as a moiety of the formula:

In another variation, Q is a substituted amino of the formula —N(H)(arylor substituted aryl), such as a moiety of the formula:

In a particular variation, Q is an amino or substituted amino and R^(8e)and R^(8f) are taken together to form a carbonyl moiety. In yet anothervariation, Q is an acylamino moiety. In still another variation, Q is anacylamino moiety and R^(8e) and R^(8f) are both hydrogen.

In another variation, Q is an alkoxy group of the formula —O—C₁-C₈alkyl,such as the moiety —O—CH₂CH₃. In yet another variation, Q is an alkoxygroup and R^(8e) and R^(8f) are taken together to form a carbonylmoiety. In still a further variation, Q is a carbonylalkoxy moiety. Inyet another variation, Q is a carbonylalkoxy moiety and R^(8e) andR^(8f) are both hydrogen.

In still another variation, Q is an acyloxy, aminocarbonylalkoxy oracylamino moiety. In one variation, Q is an acyloxy, aminocarbonylalkoxyor acylamino moiety and R^(8e) and R^(8f) are both hydrogen.

In one variation, Q is a moiety selected from the structures:

The invention also embraces compounds of the formula (I), (E), (F) or(Ia) or any variation of the foregoing detailed herein, or a compoundaccording to any one of the formulae (IIa)-(IIh), (IIIa)-(IIIo),(IVa)-(IVp) or (Va)-(Vzf) where Q is an aminoacyl moiety. In onevariation, Q is an aminoacyl group where at least one of R_(a) and R_(b)is H, such as when Q is of the formula —NHC(O)R_(b). In one variation, Qis an aminoacyl moiety selected from the group consisting of:—NHC(O)-heterocyclyl, —NHC(O)-substituted heterocyclyl, —NHC(O)-alkyl,—NHC(O)-cycloalkyl, —NHC(O)-alkaryl and —NHC(O)-substituted aryl. Inanother variation, Q is an aminoacyl moiety selected from the groupconsisting of: —NHC(O)—C₅-C₇heterocyclyl, —NHC(O)—C₁-C₆alkyl,—NHC(O)—C₃-C₇cycloalkyl, —NHC(O)—C₁-C₃alkaryl and —NHC(O)-substitutedphenyl. In a particular variation, Q is a moiety of the formula:

In one variation, a compound of the invention is of the formula (I),(E), (F) or (Ia) or any variation of the foregoing detailed herein, or acompound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf) where Q is acyloxy.

In one variation, a compound of the invention is of the formula (I),(E), (F) or (Ia) or any variation of the foregoing detailed herein, or acompound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf) where Q is a carbonylalkoxymoiety. In one variation, Q is a carbonylalkoxy moiety of the formula—C(O)—O—R¹ where R is H, alkyl, substituted alkyl or alkaryl. In onevariation, Q is carbonylalkoxy moiety of the formula —C(O)—O—C₁-C₆alkyl.In a particular variation, Q is a carbonylalkoxy moiety of the formula—C(O)—O—C₂H₅. In one variation, Q is a carbonylalkoxy moiety selectedfrom the group consisting of: —C(O)—O—C₁-C₁₀alkyl, —C(O)—O—C₁-C₃alkaryl,—C(O)—O—C₁-C₃substituted alkyl and —C(O)—OH. In another variation, Q is—C(O)—O—C₁-C₆alkyl. In a particular variation, Q is a moiety of theformula:

In yet another variation, a compound is of any formula detailed hereinand, where applicable, Q is

In another variation, a compound of the invention is of the formula (I),(E), (F) or (Ia) or any variation of the foregoing detailed herein, or acompound according to any one of the formulae (IIa)-(IIf),(IIIa)-(IIIi), (Iva)-(IVk) or (Va)-(Vzv) where Q is anaminocarbonylalkoxy moiety. In one variation, Q is anaminocarbonylalkoxy moiety of the formula —NHC(O)—O—R_(b). In anothervariation, Q is an aminocarbonylalkoxy moiety of the formula—NHC(O)—O—R_(b) where R_(b) is a substituted alkyl group. In aparticular variation, Q is a moiety of the formula—NH—C(O)—O—CH₂—C(Cl)₃.

The invention also embraces compounds of the formula (I), (E), (F) or(Ia) or any variation of the foregoing detailed herein, or a compoundaccording to any one of the formulae (IIa)-(IIf), (IIIa)-(IIIi),(Iva)-(IVk) or (Va)-(Vzv) where Q is an acylamino moiety. In onevariation, Q is an acylamino group where at least one of R_(a) and R_(b)is H, such as when Q is of the formula —C(O)N(H)(R_(b)). In anothervariation, Q is an acylamino group where both R_(a) and R_(b) alkyl. Inone variation, Q is an acylamino moiety selected from the groupconsisting of: —C(O)—N(H)(alkyl), —C(O)—N(alkyl)₂, —C(O)—N(H)(alkaryl)and —C(O)—N(H)(aryl). In another variation, Q is an acylamino moietyselected from the group consisting of: —C(O)—N(H)₂,—C(O)—N(H)(C₁-C₈alkyl), —C(O)—N(C₁-C₆alkyl)₂ and—C(O)—N(H)(C₁-C₃alkaryl). In a particular variation, Q is a moiety ofthe formula:

In yet another variation, a compound is of any formula detailed hereinand, where applicable, Q is alkynyl and is of the formula:

Any formula detailed herein, where applicable, may in one variation haveas Q the moieties detailed herein above. It is understood that by “whereapplicable” it is intended that such Q moieties be a variation if theformula encompasses such a structure. For example, if a given formuladoes not encompass structures wherein Q is a phenyl moiety, then aphenyl moiety is not applicable to that particular formula, but remainsapplicable to formulae that do encompass structures where Q is a phenylmoiety.

In a further variation, a compound of the invention is of the formula(I), (E) or (F) where R¹ is an unsubstituted alkyl, R^(2a), R^(3a),R^(3b), R¹⁰ is H, each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CH, eachR^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independently H orhydroxyl, and Q is a substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, including but not limited to a substituted orunsubstituted phenyl or pyridyl group. Where Q is a substituted phenylor pyridyl group, in one variation it is substituted with at least onemethyl group.

In yet a further variation, a compound of the invention is of theformula (I), (E) or (F) where R¹ is a substituted or unsubstituted C₁-C₈alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl; R² is H, unsubstitutedC₁-C₈ alkyl or halo; each R^(3a) and R^(3b) is independently H or halo;each X⁷, X⁸, X⁹ and X¹⁰ is CR⁴, where R⁴ is as defined in formula (I) orin a particular variation, R⁴ is H, halo, pyridyl, methyl ortrifluoromethyl; R¹⁰ is H, and Q is a substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, including but not limited to asubstituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl,imidazolyl, furanyl, pyrrolyl or thiophenyl group. In a particularvariation, Q is a pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl,furanyl, pyrrolyl or thiophenyl group substituted with at least onesubstituted or unsubstituted C₁-C₈ alkyl, halo or perhaloalkyl moiety.In one variation, a compound of the variation detailed herein isprovided wherein R¹ is propylate, methyl, ethyl, cyclopropyl,trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl,propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl,2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl,cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl,hydroxycyclopent-2-yl, hydroxycycloprop-2-yl,1-hydroxy-1-methylcycloprop-2-yl, or1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.

In still a further variation, a compound of the invention is of theformula (I), (E) or (F) where R¹ is a substituted or unsubstituted C₁-C₈alkyl; each R^(2a), R^(3a) and R^(3b) is independently H or halo; eachR⁴ is independently H, halo, C₁-C₈ perhaloalkyl, substituted or aunsubstituted C₁-C₈ alkyl; each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e)and R^(8f) is H; and Q is a substituted or unsubstituted cyclohexyl,morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinylmoiety. The invention also embraces a compound of the formula (I), (E)or (F) where R¹ is a methyl; at least one of X⁷, X⁸, X⁹ and X¹⁰ is CR⁴,and each R⁴ is independently H, halo, methyl or trifluoromethyl. Theinvention embraces compounds where Q in any variation detailed issubstituted with at least one carbonyl, hydroxymethyl, methyl orhydroxyl group.

In a particular variation, the compound is of the formula (I), (E) or(F) where R¹ is a substituted or unsubstituted C₁-C₈ alkyl; R² is H, asubstituted or unsubstituted C₁-C₈ alkyl; R^(3a) and R^(3b) are both H;each R⁴ is independently H, halo or substituted or unsubstituted C₁-C₈alkyl; each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is H; R¹⁰is H, halo, a substituted or unsubstituted C₁-C₈ alkyl, hydroxyl,alkoxyl. In one aspect of this variation, Q may be a substituted orunsubstituted pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl orthiomorpholinyl group. In another aspect of this variation, Q is apyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinylgroup substituted with at least one methyl or halo group. In yet anotheraspect of this variation, X⁷, X⁸, X⁹ and X¹⁰ are CR⁴ and each R⁴ isindependently H, halo or methyl.

In another variation, a compound of the invention is of the formula (I),(E) or (Ia) or any variation of the foregoing detailed herein, or acompound according to any one of the formulae (IIa)-(IIh),(IIIa)-(IIIo), (IVa)-(IVp) or (Va)-(Vzf) where q, m, Q and R^(8a)-R^(8f)are taken together to form a moiety of the structure:

In another variation, a compound of the invention is of the formula (E)or (F) or any applicable variation of the foregoing detailed herein,where q, m, n, Q, R^(8a)-R^(8f), R¹¹ and R¹² where applicable are takentogether to form a moiety of the structure:

In another variation, any formula detailed herein, where applicable, mayin one variation have q, m, n, Q, R^(8a)-R^(8f), R¹¹ and R¹² whereapplicable taken together to form a moiety of the structure:

Examples of compounds according to the invention are depicted in Table2. The compounds depicted may be present as salts even if salts are notdepicted and it is understood that the invention embraces all salts andsolvates of the compounds depicted here, as well as the non-salt andnon-solvate form of the compound, as is well understood by the skilledartisan.

TABLE 2 Representative Compounds According to the Invention. Ex. # Comp.# Structure  19 1

 20 2

 21 3

 22 4

 23 5

 24 6

 25 7

 26 8

 27 9

 28 10

 29 11

 30 12

 31 13

 32 14

 33 15

 34 16

 35 17

 36 18

 37 19

 38 20

 39 21

 40 22

 41 23

 42 24

 43 25

 44 26

 45 27

 46 28

 47 29

 48 30

 49 31

 50 32

 51 33

 52 34

 53 35

 54 36

 55 37

 56 38

 57 39

 58 40

 59 41

 60 42

 61 43

 62 44

 63 45

 64 46

145 47

145 48

145 49

145 50

145 51

 94 52

 95 53

 81 54

 69 55

 82 56

 75 57

 87 58

 83 59

 84 60

 85 61

 86 62

145 63

 76 64

 77 65

 78 66

 79 67

145 68

145 69

 71 70

 70 71

 72 72

145 73

145 74

145 75

145 76

 90 77

 91 78

 68 79

 92 80

 67 81

 89 82

 88 83

145 84

145 85

 93 86

145 87

145 88

145 89

 74 90

 80 91

 66 92

145 93

145 94

145 95

145 96

110 97

111 98

112 99

113 100

145 101

145 102

145 103

145 104

145 105

116 106

117 107

114 108

102 109

103 110

 98 111

 97 112

115 113

 96 114

105 115

104 116

118 117

119 118

120 119

121 120

 99 121

100 122

122 123

123 124

65, 73 125

145 126

145 127

106 128

101 129

107 130

145 131

108 132

145 133

145 134

145 135

145 136

145 137

145 138

145 139

145 140

145 141

145 142

145 143

145 144

145 145

145 146

145 147

145 148

145 149

145 150

145 151

145 152

145 153

145 154

109 155

145 156

145 157

145 158

124 159

125 160

126 161

127 162

128 163

129 164

130 165

131 166

132 167

133 168

134 169

135 170

136 171

137 172

138 173

139 174

140 175

141 176

142 177

143 178

145 179

145 180

145 181

145 182

145 183

144 184

Pharmaceutical compositions of any of the compounds detailed herein areembraced by this invention. Thus, the invention includes pharmaceuticalcompositions comprising a compound of the invention or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or excipient. Pharmaceutical compositions accordingto the invention may take a form suitable for oral, buccal, parenteral,nasal, topical or rectal administration, or a form suitable foradministration by inhalation.

Compounds of the invention, such as compounds of the formula 1,including compounds listed in Table 1, may be used in a method ofmodulating a histamine receptor.

In one variation, the compounds herein are synthetic compounds preparedfor administration to an individual. In another variation, compositionsare provided containing a compound in substantially pure form. Inanother variation, the invention embraces pharmaceutical compositionscomprising a compound detailed herein and a pharmaceutically acceptablecarrier. In another variation, methods of administering a compound areprovided. The purified forms, pharmaceutical compositions and methods ofadministering the compounds are suitable for any compound or formthereof detailed herein.

General Description of Biological Assays

The binding properties of compounds disclosed herein to a panel ofaminergic G protein-coupled receptors including adrenergic receptors,dopamine receptors, serotonin receptors, histamine receptors and animidazoline receptor may be determined. Binding properties may beassessed by methods known in the art, such as competitive bindingassays. In one variation, compounds are assessed by the binding assaysdetailed herein. Compounds disclosed herein may also be tested incell-based assays or in in vivo models for further characterization. Inone aspect, compounds disclosed herein are of any formula detailedherein and further display one or more of the following characteristics:inhibition of binding of a ligand to an adrenergic receptor (e.g., α1D,α2A and α2B), inhibition of binding of a ligand to a serotonin receptor(e.g., 5-HT2A, 5-HT2C, 5-HT6 and 5-HT7), inhibition of binding of aligand to a dopamine receptor (e.g., D2L), and inhibition of binding ofa ligand to a histamine receptor (e.g., H1, H2 and H3);agonist/antagonist activity to a serotonin receptor (e.g., 5-HT2A,5-HT6); agonist/antagonist activity to a dopamine receptor (e.g., D2L,D2S); agonist/antagonist activity to a histamine receptor (e.g., H1);activity in a neurite outgrowth assay; efficacy in a preclinical modelof memory dysfunction associated with cholinergicdysfunction/hypofunction; and efficacy in a preclinical model ofschizophrenia.

In one variation, inhibition of binding of a ligand to a receptor ismeasured in the assays described herein. In another variation,inhibition of binding of a ligand is measured in an assay known in theart. In one variation, binding of a ligand to a receptor is inhibited byat least about 80% as determined in a suitable assay known in the artsuch as the assays described herein. In one variation, binding of aligand to a receptor is inhibited by greater than about any one of 80%,85%, 90%, 95%, 100%, or between about 85-95% or between about 90-100% asdetermined in a suitable assay known in the art such as the assaysdescribed herein. In one variation, binding of a ligand to a receptor isinhibited by at least about 80%±20% as determined in an assay known inthe art.

In one variation, a compound of the invention inhibits binding of aligand to at least one receptor and as many as eleven as detailed herein(e.g. α1D, α2A, α2B, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D2L, H1, H2, H3). Inone variation, a compound of the invention inhibits binding of a ligandto at least one and as many as eleven receptors detailed herein andfurther displays agonist or antagonist activity to one or more receptorsdetailed herein (e.g., serotonin receptor 5-HT2A, serotonin receptor5-HT6, dopamine receptor D2L, and dopamine receptor D2S, histaminereceptor H1) as measured in the assays described herein. In onevariation, agonist response of serotonin receptor 5-HT2A is inhibited bycompounds of the invention by at least about any one of 50%, 50%, 70%,80%, 90%, 100%, 110%, 120%, 130%, 140%, 150% as determined in a suitableassay such as the assay described herein.

In one variation, a compound of the invention displays the abovedescribed neurotransmitter receptor binding profile i.e. inhibitsbinding of a ligand to at least one receptor and as many as eleven asdetailed herein and further stimulates neurite outgrowth, e.g. asmeasured by the assays described herein. Certain compounds of theinvention showed activity in neurite outgrowth assays using primaryneurons in culture (see Example 11B). Data is presented indicating thata compound of the invention has activity comparable in magnitude to thatof naturally occurring prototypical neurotrophic proteins such as brainderived neurotrophic factor (BDNF) and nerve growth factor (NGF).Notably, neurite outgrowth plays a critical part of new synaptogenesis,which is beneficial for the treatment of neuronal disorders. In onevariation, neurite outgrowth is observed with a potency of about 1 μM asmeasured in a suitable assay known in the art such as the assaysdescribed herein. In another variation, neurite outgrowth is observedwith a potency of about 500 nM. In a further variation, neuriteoutgrowth is observed with a potency of about 50 nM. In anothervariation, neurite outgrowth is observed with a potency of about 5 nM.

In another variation, a compound of the invention inhibits binding of aligand to at least one receptor and as many as eleven as detailedherein, further displays agonist or antagonist activity to one or morereceptors detailed herein and further stimulates neurite outgrowth.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors as detailedherein and/or display the above described neurotransmitter receptorbinding profile and further shows efficacy in a preclinical model ofmemory dysfunction associated with cholinergic dysfunction/hypofunction,i.e. shows pro-cognitive effects in a preclinical model of memorydysfunction. As H1 antagonism may contribute to sedation, weight gainand reduced cognition, low affinity (less than about 80% inhibition ofbinding of Pyrilamine at 1 μM in the assay described herein) for thisreceptor may be associated with pro-cognitive effects and a moredesirable side effect profile. Furthermore, compounds of the inventionwith increased potency as a 5-HT6 antagonist may havecognition-enhancing effects as serotonin acting through this receptormay impair memory.

In another variation, a compound of the invention inhibits at least oneand as many as eleven receptors as detailed herein, further showsefficacy in a preclinical model of memory dysfunction associated withcholinergic dysfunction/hypofunction i.e. shows pro-cognitive effects ina preclinical model of memory dysfunction and further displays agonistor antagonist activity to one or more receptors detailed herein.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors as detailedherein, further shows efficacy in a preclinical model of memorydysfunction associated with cholinergic dysfunction/hypofunction i.e.shows pro-cognitive effects in a preclinical model of memory dysfunctionand further stimulates neurite outgrowth.

In another variation, a compound of the invention inhibits at least oneand as many as eleven receptors as detailed herein, further showsefficacy in a preclinical model of memory dysfunction associated withcholinergic dysfunction/hypofunction i.e. shows pro-cognitive effects ina preclinical model of memory dysfunction, further displays agonist orantagonist activity to one or more receptor detailed herein and furtherstimulates neurite outgrowth.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors and furtherpossesses anti-psychotic effects as measured in a preclinical model ofschizophrenia, i.e., shows efficacy in a preclinical model ofschizophrenia.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia and further displaysagonist or antagonist activity to one or more receptors detailed herein.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia and further stimulatesneurite outgrowth.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of memory dysfunction associated withcholinergic dysfunction/hypofunction such as enhancement of memoryretention and reduction of memory impairment, and further shows efficacyin a preclinical model of schizophrenia.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia, further displaysagonist or antagonist activity to one or more receptors detailed hereinand further shows efficacy in a preclinical model of memory dysfunctionassociated with cholinergic dysfunction/hypofunction such as enhancementof memory retention and reduction of memory impairment.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia, further stimulatesneurite outgrowth and further shows efficacy in a preclinical model ofmemory dysfunction associated with cholinergic dysfunction/hypofunctionsuch as enhancement of memory retention and reduction of memoryimpairment.

In a further variation, a compound of the invention inhibits binding toat least one and as many as eleven receptors detailed herein, furtherdisplays agonist or antagonist activity to one or more receptorsdetailed herein, further stimulates neurite outgrowth and further showsefficacy in a preclinical model of schizophrenia.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia, further displaysagonist or antagonist activity to one or more receptors detailed herein,further stimulates neurite outgrowth and further shows efficacy in apreclinical model of memory dysfunction associated with cholinergicdysfunction/hypofunction such as enhancement of memory retention andreduction of memory impairment.

In another variation, a compound of the invention stimulates neuriteoutgrowth. In another variation, a compound of the invention showsefficacy in a preclinical model of schizophrenia and further stimulatesneurite outgrowth. In another variation, a compound of the inventionstimulates neurite outgrowth and further shows efficacy in a preclinicalmodel of memory dysfunction associated with cholinergicdysfunction/hypofunction such as enhancement of memory retention andreduction of memory impairment. In another variation, a compound of theinvention shows efficacy in a preclinical model of schizophrenia,further stimulates neurite outgrowth and further shows efficacy in apreclinical model of memory dysfunction associated with cholinergicdysfunction/hypofunction such as enhancement of memory retention andreduction of memory impairment.

In one aspect, compounds of the invention inhibit binding of a ligand toadrenergic receptors α1D, α2A, α2B and inhibit binding of a ligand toserotonin receptor 5-HT6. In another variation, compounds of theinvention inhibit binding of a ligand to adrenergic receptors α1D, α2A,α2B, to serotonin receptor 5-HT6 and to any one or more of the followingreceptors: serotonin receptor 5-HT7, 5-HT2A and 5-HT2C. In anothervariation, compounds of the invention inhibit binding of a ligand toadrenergic receptors α1D, α2A, α2B, to serotonin receptor 5-HT6 and toany one or more of the following receptors: serotonin receptor 5-HT7,5-HT2A and 5-HT2C and further show weak inhibition of binding of aligand to histamine receptor H1 and/or H2. In one variation, compoundsof the invention that also display strong inhibition of binding of aligand to the serotonin receptor 5-HT7 are particularly desired. Inanother variation, compounds of the invention inhibit binding of aligand to adrenergic receptors α1D, α2A, α2B, to serotonin receptor5-HT6 and further show weak inhibition of binding of a ligand tohistamine receptor H1 and/or H2. Weak inhibition of binding of a ligandto the histamine H1 receptor is permitted as agonists of this receptorhave been implicated in stimulating memory as well as weight gain. Inone variation, binding to histamine receptor H1 is inhibited by lessthan about 80%. In another variation, binding of a ligand to histaminereceptor H1 is inhibited by less than about any of 75%, 70%, 65%, 60%,55%, or 50% as determined by a suitable assay known in the art such asthe assays described herein.

In another variation, compounds of the invention inhibit binding of aligand to dopamine receptor D2L. In another variation, compounds of theinvention inhibit binding of a ligand to dopamine receptor D2L and toserotonin receptor 5-HT2A. In another variation, compounds of theinvention inhibit binding of a ligand to histamine receptor H1. Incertain aspects, compounds of the invention further show one or more ofthe following properties: strong inhibition of binding of a ligand tothe serotonin 5-HT7 receptor, strong inhibition of binding of a ligandto the serotonin 5-HT2A receptor, strong inhibition of binding of aligand to the serotonin 5-HT2C receptor, weak inhibition of binding of aligand to the histamine H1 receptor, weak inhibition of binding ofligands to the histamine H2 receptor, and antagonist activity toserotonin receptor 5-HT2A.

In one variation, compounds of the invention show any of the receptorbinding aspects detailed herein and further display agonist/antagonistactivity to one or more of the following receptors: serotonin receptor5-HT2A, serotonin receptor 5-HT6, dopamine receptor D2L, dopaminereceptor D2S and histamine receptor H1. In one variation, compounds ofthe invention show any of the receptor binding aspects detailed hereinand further stimulate neurite outgrowth. In one variation, compounds ofthe invention show any of the receptor binding aspects detailed hereinand further show efficacy in a preclinical model of memory dysfunctionassociated with cholinergic dysfunction/hypofunction. In one variation,compounds of the invention show any of the receptor binding aspectsdetailed herein and further show efficacy in a preclinical model ofschizophrenia. In one variation, compounds of the invention show any ofthe receptor binding aspects detailed herein and further show efficacyin any one or more of agonist/antagonist assays (e.g., to serotoninreceptor 5-HT2A, 5-HT6, dopamine receptor D2L, dopamine receptor D2S andhistamine receptor H1), neurite outgrowth, a preclinical model of memorydysfunction associated with cholinergic dysfunction/hypofunction and apreclinical model of schizophrenia.

In some aspects, compounds of the invention inhibit binding of a ligandto adrenergic receptors α1D, α2A, α2B, serotonin receptor 5-HT6 anddopamine receptor D2L by at least about 80% as determined in a suitableassay known in the art such as the assays described herein. In onevariation binding is inhibited by at least about 80% as measured in asuitable assay such as the assays described herein. In one variation,binding of a ligand to a receptor is inhibited by greater than about anyone of 80%, 85%, 90%, 95%, 100%, or between about 85% and about 95%, orbetween about 90% and about 100% as determined in a suitable assay knownin the art such as the assays described herein.

In some aspects, compounds of the invention display the above describedneurotransmitter receptor binding profile and further show antipsychoticeffects. It is recognized that compounds of the invention have bindingprofiles similar to compounds with antipsychotic activity. In addition,compounds of the invention might possess the cognitive enhancingproperties of dimebon and thus add to the beneficial pharmacologyprofile of these antipsychotic molecules. In one variation, compounds ofthe invention display the above described neurotransmitter receptorbinding profile and further show pro-cognitive effects in a preclinicalmodel of memory dysfunction such as enhancement of memory retention andreduction of memory impairment due to cholinergic hypofunction inpreclinical animal models. In another variation, compounds of theinvention display the above described neurotransmitter receptor bindingprofile and do not show pro-cognitive effects in a preclinical model ofmemory dysfunction, learning and memory.

In one variation, compounds of the invention demonstrate pro-cognitiveeffects in a preclinical model of memory dysfunction, learning andmemory. In a further variation, compounds of the invention possessanti-psychotic effects in a preclinical model of schizophrenia. In afurther variation, compounds of the invention demonstrate pro-cognitiveeffects in a preclinical model of memory dysfunction, learning andmemory and further possess anti-psychotic effects in a preclinical modelof schizophrenia.

Overview of the Methods

The compounds described herein may be used to treat, prevent, delay theonset and/or delay the development of cognitive disorders, psychoticdisorders, neurotransmitter-mediated disorders and/or neuronal disordersin individuals, such as humans. In one aspect, the compounds describedherein may be used to treat, prevent, delay the onset and/or delay thedevelopment of a cognitive disorder. In another aspect, the compoundsdescribed herein may be used to treat, prevent, delay the onset and/ordelay the development of a psychotic disorder. In yet another aspect,the compounds described herein may be used to treat, prevent, delay theonset and/or delay the development of a neurotransmitter-mediateddisorders disorder. In one embodiment, the neurotransmitter-mediateddisorder includes spinal cord injury, diabetic neuropathy, allergicdiseases (including food allergies) and diseases involvinggeroprotective activity such as age-associated hair loss (alopecia),age-associated weight loss and age-associated vision disturbances(cataracts). In another variation, the neurotransmitter-mediateddisorder includes spinal cord injury, diabetic neuropathy, fibromyalgiaand allergic diseases (including food allergies). In still anotherembodiment, the neurotransmitter-mediated disorder includes Alzheimer'sdisease, Parkinson's Disease, autism, Guillain-Barré syndrome, mildcognitive impairment, multiple sclerosis, stroke and traumatic braininjury. In yet another embodiment, the neurotransmitter-mediateddisorder includes schizophrenia, anxiety, bipolar disorders, psychosisand depression. In another aspect, the compounds described herein may beused to treat, prevent, delay the onset and/or delay the development ofa neuronal disorder. In one aspect, the compounds described herein mayalso be used to treat, prevent, delay the onset and/or delay thedevelopment of cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders for whichthe modulation of an aminergic G protein-coupled receptor is believed tobe or is beneficial.

The invention also provides methods of improving cognitive functionsand/or reducing psychotic effects comprising administering to anindividual in need thereof an amount of a compound of the invention or apharmaceutically acceptable salt thereof effective to improve cognitivefunctions and/or reduce psychotic effects.

The invention also provides methods of stimulating neurite outgrowthand/or promoting neurogenesis and/or enhancing neurotrophic effects inan individual comprising administering to an individual in need thereofan amount of a compound of the invention or a pharmaceuticallyacceptable salt thereof effective to stimulate neurite outgrowth and/orto promote neurogenesis and/or to enhance neurotrophic effects.

The invention further encompasses methods of modulating an aminergic Gprotein-coupled receptor comprising administering to an individual inneed thereof an amount of a compound of the invention or apharmaceutically acceptable salt thereof effective to modulate anaminergic G protein-coupled receptor.

It is to be understood that methods described herein also encompassmethods of administering compositions comprising the compounds of theinvention.

Methods for Treating, Preventing, Delaying the Onset, and/or Delayingthe Development Cognitive Disorders, Psychotic Disorders,Neurotransmitter-mediated Disorders and/or Neuronal Disorders

In one aspect, the invention provides methods for treating, preventing,delaying the onset, and/or delaying the development of cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders for which the modulation of an aminergic Gprotein-coupled receptor is believed to be or is beneficial, the methodcomprising administering to an individual in need thereof a compound ofthe invention. In some variations, modulation of adrenergic receptorα1D, α2A, α2B, serotonin receptor 5-HT2A, 5-HT6, 5HT7, histaminereceptor H1 and/or H2 is expected to be or is beneficial for thecognitive disorders, psychotic disorders, neurotransmitter-mediateddisorders and/or neuronal disorders. In some variations, modulation ofadrenergic receptor α1D, α2A, α2B and a serotonin receptor 5-HT6receptor is expected to be or is beneficial for the cognitive disorders,psychotic disorders, neurotransmitter-mediated disorders and/or neuronaldisorders. In some variations, modulation of adrenergic receptor α1D,α2A, α2B, and a serotonin receptor 5-HT6 receptor and modulation of oneor more of the following receptors serotonin 5-HT7, 5-HT2A, 5-HT2C andhistamine H1 and H2 is expected to be or is beneficial for the cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders. In some variations, modulation of dopaminereceptor D2L is expected to be or is beneficial for the cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders. In certain variations, modulation of adopamine D2L receptor and serotonin receptor 5-HT2A is expected to be oris beneficial for the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders. In somevariations, the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders aretreated, prevented and/or their onset or development is delayed byadministering a compound of the invention.

Methods to Improve Cognitive Functions and/or Reduce Psychotic Effects

The invention provides methods for improving cognitive functions byadministering a compound of the invention to an individual in needthereof. In some variations, modulation of one or more of adrenergicreceptor α1D, α2A, α2B, serotonin receptor 5-HT2A, 5-HT6, 5HT7,histamine receptor H1 and/or H2 is desirable or expected to be desirableto improve cognitive functions. In some variations modulation of α1D,α2A, α2B adrenergic receptors and a serotonin 5-HT6 receptor isdesirable or expected to be desirable to improve cognitive functions. Insome variations, modulation of α1D, α2A, α2B adrenergic receptors andserotonin receptor 5-HT6 and modulation of one or more of the followingreceptors: serotonin receptor 5-HT7, 5-HT2A, 5-HT2C and histaminereceptor H1 and H2, is desirable or expected to be desirable to improvecognitive functions. In another aspect, the invention encompassesmethods to reduce psychotic effects by administering a compound of theinvention to an individual in need thereof. In some embodiments,modulation of a dopamine D2L receptor is expected to be or is desirableto reduce psychotic effects. In some embodiments, modulation of adopamine D2L receptor and a serotonin 5-HT2A receptor is expected to beor is desirable to reduce psychotic effects. In some variations, acompound of the invention is administered to an individual in needthereof.

Methods to Stimulate Neurite Outgrowth, Promote Neurogenesis and/orEnhance Neurotrophic Effects

In a further aspect, the invention provides methods of stimulatingneurite outgrowth and/or enhancing neurogenesis and/or enhancingneurotrophic effects comprising administering a compound of theinvention or pharmaceutically acceptable salt thereof under conditionssufficient to stimulate neurite outgrowth and/or to enhance neurogenesisand/or enhance neurotrophic effects to an individual in need thereof. Insome variations, a compound of the invention stimulates neuriteoutgrowth at a potency of about 1 μM as measured in a suitable assaysuch as the assays described herein. In some variations, a compound ofthe invention stimulates neurite outgrowth at a potency of about 500 nMas measured in a suitable assay such as the assays described herein. Insome variations, a compound of the invention stimulates neuriteoutgrowth at a potency of about 50 nM as measured in a suitable assaysuch as the assays described herein. In some variations, a compound ofthe invention stimulates neurite outgrowth at a potency of about 5 nM asmeasured in a suitable assay such as the assays described herein.

Methods to Modulate an Aminergic G Protein-Coupled Receptor

The invention further contemplates methods for modulating the activityof an aminergic G-protein-coupled receptor comprising administering acompound of the invention or pharmaceutically acceptable salt thereofunder conditions sufficient to modulate the activity of an aminergic Gprotein-coupled receptor. In some variations, the aminergic Gprotein-coupled receptor is a α1D, α2A, α2B adrenergic receptor and aserotonin 5-HT6 receptor. In some variations, the aminergic Gprotein-coupled receptor is a α1D, α2A, α2B adrenergic receptor and aserotonin 5-HT6 and 5-HT7 receptor. In some variations, the aminergic Gprotein-coupled receptor is a α1D, α2A, α2B adrenergic receptor, aserotonin 5-HT6 and one or more of the following receptors: serotonin5-HT-7,5-HT2A and 5-HT2C and histamine H1 and H2 receptor. In somevariations, the aminergic G protein-coupled receptor is a dopamine D2Lreceptor. In some variations, the aminergic G protein-coupled receptoris a dopamine D2L receptor and a serotonin 5-HT2A receptor. In somevariations, the aminergic G protein-coupled receptor is a histamine H1receptor.

General Synthetic Methods

The compounds of the invention may be prepared by a number of processesas generally described below and more specifically in the Exampleshereinafter. In the following process descriptions, the symbols whenused in the formulae depicted are to be understood to represent thosegroups described above in relation to formula (I) or a variation thereofunless otherwise indicated.

Where it is desired to obtain a particular enantiomer of a compound,this may be accomplished from a corresponding mixture of enantiomersusing any suitable conventional procedure for separating or resolvingenantiomers. Thus, for example, diastereomeric derivatives may beproduced by reaction of a mixture of enantiomers, e.g. a racemate, andan appropriate chiral compound. The diastereomers may then be separatedby any convenient means, for example by crystallization and the desiredenantiomer recovered. In another resolution process, a racemate may beseparated using chiral High Performance Liquid Chromatography.Alternatively, if desired a particular enantiomer may be obtained byusing an appropriate chiral intermediate in one of the processesdescribed.

Chromatography, recrystallization and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular isomer of a compound or tootherwise purify a product of a reaction.

The following abbreviations are used herein: thin layer chromatography(TLC); Hour (h); Ethanol (EtOH); dimethylsulfoxide (DMSO);N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); tetrahydrofuran(THF); Normal (N); aqueous (aq.); methanol (MeOH); dichloromethane(DCM); Retention factor (Rf).

General methods of preparing compounds according to the invention aredepicted in exemplified methods below. Other compounds of the inventionmay be prepared by similar methods. For example, Scheme 1b is anexemplified synthesis of the method detailed in Scheme Ia but othercompounds of the invention may be prepared by similar methods.

A method of synthesizing an intermediate used in the synthesis ofcompounds of the invention is shown as General Methods 1-15.

General Method 1

Arylhydrazine hydrochloride (1 equiv) is mixed with triethylamine (3equiv) and alkyl halide (1 equiv) at 25° C. The reaction mixture isstirred at RT for 1 h and subsequently heated at 90° C. until completionof the reaction as determined by TLC and LC-MS (approx for 16 h).Reaction mixture is concentrated under reduced pressure, diluted withwater and extracted with ethyl acetate. The combined organic layer isdried (Na₂SO₄) and concentrated to obtain crude product which ispurified by column chromatography (silica gel, 100-200 mesh, eluent:ethyl acetate-hexanes gradient).

General Method 2

Arylhydrazine hydrochloride (1 equiv) is added to a vigorously stirredmixture of tetra-n-butylammonium chloride (0.05 equiv) in 50% aqueoussodium hydroxide (1 mL/mmol of arylhydrazine hydrochloride) followed byalkyl halide (1.1 equiv). The mixture is heated at 60° C. (oil bathtemp.) for 6 h. After cooling to room temperature, water is added andthe mixture is extracted with chloroform. The total extract is dried(sodium sulfate) and evaporated in vacuo to furnish crude product thatis purified by column chromatography (silica gel, 100-200 mesh, eluent:eluent: ethyl acetate-hexanes gradient or dichloromethane).

General Method 3

The hydrazine derivative (1 equiv) is converted into the correspondingHCl salt and dissolved in water. The appropriate acetal (1 equiv) isadded and the mixture is heated at 0-90° C. for 3-6 h. The reactionmixture is cooled to RT, and saturated aqueous NaHCO₃ is added. Theproduct is extracted with ethyl acetate. Concentration of the combinedorganic layers under vacuum yields crude product that is purified bychromatography on silica gel to obtain the product.

General Method 4

A solution of appropriate tryptamine derivative (1 equiv), formaldehyde(1 equiv) in acetonitrile containing 5% TFA (8-10 mL/mmol) is stirred atreflux for 15 min-2 h. The reaction mixture is cooled to 25° C.,concentrated under reduced pressure and partitioned between ethylacetate and satd. aqueous NaHCO₃. The organic layer is dried over sodiumsulfate, evaporated under reduced pressure and the residue is purifiedby silica gel chromatography to obtain the product.

General Method 5

A mixture of appropriate carboline derivative with side chaincarboxylate ester (1 equiv) and NaOH (3N, 5 folds w/v) in ethanol (5folds w/v) is stirred at 50° C. for 3 h after which it is cooled to RTand neutralized with conc. HCl. The solvent is removed under reducedpressure to obtain corresponding crude carboxylic acid. The resultingcrude product is purified by silica gel chromatography (100-200 mesh or230-400 mesh) using methanol-dichloromethane gradient, by neutralalumina using ethyl acetate-hexane gradient, and/or by reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL).

General Method 6

A mixture of appropriate carboline derivative with side chain carboxylicacid (1 equiv) is stirred with appropriate alcohol (1 equiv), EDCI-HCl(1 equiv) and triethylamine (1 equiv) in dichloromethane for 12-16 h.The reaction mixture is evaporated under vacuo to obtain the crude esterthat is purified by silica gel chromatography (100-200 mesh or 230-400mesh) using methanol-dichloromethane gradient, by neutral alumina usingethyl acetate-hexane gradient, and/or by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

General Method 7

A mixture of appropriate carboline derivative with side chain carboxylicacid (1 equiv) is stirred with appropriate amine (1 equiv), EDCI-HCl (1equiv) and triethylamine (1 equiv) in dichloromethane for 12-16 h. Thereaction mixture is evaporated in vacuo to obtain the crude amide thatis purified by silica gel chromatography (100-200 mesh or 230-400 mesh)using methanol-dichloromethane gradient, by neutral alumina using ethylacetate-hexane gradient, and/or by reverse-phase chromatography (C-18,500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).

General Method 8

Carboline derivative (1 equiv), epoxide derivative (4-7.5 equiv) and NaH(3 equiv) are heated in DMF (3 mL/mmol) at 120° C. for 16 h. Thecontents are quenched by methanol and evaporated to dryness. Theresulting crude product is purified by silica gel chromatography(100-200 mesh or 230-400 mesh) using methanol-dichloromethane gradient,by neutral alumina using ethyl acetate-hexane gradient, and/or byreverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05%TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in30 min, injection vol. 5 mL).

General Method 9

Appropriate carboline (1 equiv) is dissolved in NMP (0.6 mL/mmol).Powdered KOH (3.5 equiv) is added to this solution, and the reactionmixture is stirred for 10 min at 25° C. Appropriate vinylpyridinederivative (1.1 equiv) is added and the reaction mixture is heated insealed tube at 45° C. for 30 min. The reaction is monitored by LCMS.After this period, the reaction mixture is cooled to 25° C. and dilutedwith satd. aqueous NaCl (5 mL). The product is extracted with ethylacetate. The combined organic layer is dried over anhydrous sodiumsulfate and evaporated under reduced pressure. The resulting crudeproduct is purified by silica gel chromatography (100-200 mesh or230-400 mesh) using methanol-dichloromethane gradient, by neutralalumina using ethyl acetate-hexane gradient, and/or by reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol. 5 mL).

General Method 10

A solution of 4% aqueous sulfuric acid (5 mL) is heated to 50° C. over30-60 min. Nitrogen is bubbled through the solution as it is heated todisplace dissolved air. The hydrazine derivative (1 mmol) is added tothe heated mixture, and the solid is allowed to dissolve. Theappropriate acetal (1.2 mmol) is then added as a stream over 30 min, andthis mixture is heated at reflux for 2 h. The reaction mixture is cooledto rt, and 30% aqueous ammonium hydroxide (0.5 mL) is added drop wisemaintaining the temperature at 25-30° C. The product is extracted withethyl acetate. Concentration of the combined organic layers under vacuumyield a crude product that is purified by chromatography on silica gelusing ethyl acetate: ethanol: NH₄OH 7:3:1.

General Method 11

A mixture of appropriate tryptamine derivative (1.0 mmol), formaldehyde(1.0 mmol) and TFA (0.15 mL) in acetonitrile (3 mL) is stirred at 25° C.for 20 h. The solution is quenched with saturated aqueous NaHCO₃solution. The organic layer is separated, washed with brine and driedwith MgSO₄. The solvent is removed under reduced pressure. Flashchromatography (10% CH₃OH/CH₂Cl₂) allowed isolation of product as thickoil.

General Method 12

General method for the preparation of compounds using Scheme II, asexemplified for the synthesis of Compound 6 (Scheme 11(a), Example 24):A suitably substituted phenyl hydrazine is reacted with a 4 carbonprotected amino acetal or aldehyde (U.S. Pat. No. 2,642,438) to generatea substituted 3-(2-aminoethyl)indole. This 3-(2-aminoethyl)indole canthen be reacted with formaldehyde, under standard Pictet Spinglerreaction conditions (Org. Lett. 2003, 5 (1), 43-46) to give anN-unsubstituted β-carboline. This β-carboline can then be reacted witharyl and/or heteroaryl groups bearing a vinyl substituent to install theside chain denoted by Q in synthetic scheme II.

General Method 13

General method for the preparation of compounds using Scheme III asexemplified for the synthesis of Compound 7 (Scheme 111(a), Example 25):A suitably substituted phenyl hydrazine is reacted with a 4 carbonprotected amino acetal or aldehyde (U.S. Pat. No. 2,642,438) to generatea substituted 3-(2-aminoethyl)indole. This 3-(2-aminoethyl)indole canthen be reacted with formaldehyde, under standard Pictet Spinglerreaction conditions (U.S. Pat. No. 2,642,438) to give an N-unsubstitutedβ-carboline. This β-carboline can then be reacted with aryl and/orheteroaryl styrene oxides (carboline, aryl/heteroaryl oxide, NaH, DMF,120° C.) to install the side chain denoted by Q in synthetic scheme III.

General Method 14

General method for the preparation of compounds using Scheme IV asexemplified for the synthesis of Compound 14 (Scheme IV(a), Example 32):A suitably substituted phenyl hydrazine is reacted with an alkyl halidebearing an ester functionality, followed by a reaction with a 4 carbonprotected amino acetal or aldehyde (U.S. Pat. No. 2,642,438) to generatea substituted 3-(2-aminoethyl)indole. This 3-(2-aminoethyl)indole canthen be reacted with formaldehyde, under standard Pictet Spinglerreaction conditions (U.S. Pat. No. 2,642,438) to give an N-substitutedβ-carboline. This β-carboline is then treated with base to affect thehydrolysis of the ester functionality leading to the generation of afree acid. This acid can then be reacted with an alkyl, aryl and/orheteroaryl primary or secondary amine (carboline derivative with sidechain carboxylic acid, appropriate primary or secondary amine, EDCI andtriethylamine in dichloromethane for 12-16 h) to install the side chaindenoted by R₂ and R₃ in Scheme IV.

General Method 15

General method for the preparation of compounds using Scheme V asexemplified for the synthesis of Compound 19 (Scheme V(a), Example 37):A suitably substituted phenyl hydrazine is reacted with an alkyl halidebearing an ester functionality, followed by a reaction with a 4 carbonprotected amino acetal or aldehyde (U.S. Pat. No. 2,642,438) to generatea substituted 3-(2-aminoethyl)indole. This 3-(2-aminoethyl)indole canthen be reacted with formaldehyde, under standard Pictet Spinglerreaction conditions (U.S. Pat. No. 2,642,438) to give an N-substitutedβ-carboline. This β-carboline is then treated with base to affect thehydrolysis of the ester functionality leading to the generation of afree acid. This acid can then be reacted with an alkyl, aryl and/orheteroaryl primary alcohol (carboline derivative with side chaincarboxylic acid, appropriate alcohol, EDCI and triethylamine indichloromethane for 12-16 h) to install the side chain denoted by R₂ inScheme V.

General Method 16

Appropriate carboline (1 equiv, 84 mg, 0.34 mmol) is dissolved in DMF(15 mL/mmol). To this solution is added CuI (10 mol %, 6 mg, 0.034mmol), L-proline (20 mol %, 8 mg, 0.068 mmol), K₃PO₄ (2 equiv). Thereaction mixture is stirred for 10 min at room temperature followed byaddition of 4-(1-bromoprop-1-en-2-yl)-2-fluoro-1-methoxybenzene (1.2equiv). The reaction mixture is heated at 80° C. for 18 h. Solvent isevaporated under reduced pressure, the residue is diluted with brine andextracted with ethyl acetate. Organic layer is dried over Na₂SO₄, andconcentrated under reduced pressure. The crude product is purified bysilica gel chromatography.

General Method 17

Appropriate beta-carboline (1 equiv.) is mixed with CuSO₄.5H₂O (20 mol%), 1,10-phenanthroline (0.4 equiv), K₃PO₄ (2 equiv) and appropriatevinyl bromide (1.1 equiv) in toluene (5 ml). The reaction mixture ispurged with nitrogen and heated at 80° C. for 16 h. The reaction mixtureis filtered through Celite and Celite bed is rinsed withdichloromethane. Combined organic layer is concentrated under reducedpressure and the residue is purified by silica gel chromatography(100-200 mesh) eluting with 60-80% ethyl acetate in hexane to obtain theproduct.

General Methods for HPLC Analysis

Column: Phenomenex Gemini C18, 50 mm×4.6 mm.

Mobile Phase A: Acetonitrile, B: 10 mM Ammonium Acetate in Water.

Column Temp: 40° C.

Flow Rate: 1 ml/min.

Gradient: 20% A, 0.3 min hold, 20% A to 90% A 0.3-4.0 min, 90% A hold 1min, 5.03-7.00 min 20% A.

The methods detailed above may be adapted as known by those of skill inthe art. Particular examples of each General Method are provided in theExamples below.

The following Examples are provided to illustrate but not limit theinvention.

All references disclosed herein are incorporated by reference in theirentireties.

EXAMPLES Example 1 Preparation of1-(4-chlorophenyl)-1-(2-(2-methylpyrimidin-5-yl)ethyl)hydrazine

The preparation of title compound is carried out by General Method 2using 4-chlorophenyl hydrazine hydrochloride and5-(2-bromoethyl)-2-methylpyrimidine.

Example 2 Preparation of1-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1-p-tolylhydrazine

The preparation of title compound is carried out by General Method 2using 4-chlorophenyl hydrazine hydrochloride and5-(2-bromoethyl)-2-(trifluoromethyl)pyridine.

Example 3 Preparation of1-(4-chlorophenyl)-1-(2-(piperidin-1-yl)ethyl)hydrazine

The preparation of title compound is carried out by General Method 2using 4-chlorophenyl hydrazine hydrochloride and1-(2-chloroethyl)piperidine hydrochloride.

Example 4 Preparation of1-(4-chlorophenyl)-1-(2-cyclopentylethyl)hydrazine

The preparation of title compound is carried out by General Method 2using 4-chlorophenyl hydrazine hydrochloride and(2-bromoethyl)cyclopentane.

Example 5 Preparation of1-(4-chlorophenyl)-1-(2-(3,3-dimethylcyclopentyl)ethyl)hydrazine

The preparation of title compound is carried out by General Method 2using 4-chlorophenyl hydrazine hydrochloride and3-(2-chloroethyl)-1,1-dimethylcyclopentane.

Example 6 Preparation of2-(1-(4-chlorophenyl)hydrazinyl)-1-(4-methylpiperidin-1-yl)ethanone

The preparation of title compound is carried out by General Method 2using 4-chlorophenyl hydrazine hydrochloride and2-chloro-1-(4-methylpiperidin-1-yl)ethanone.

Example 7 Preparation of2-(1-(4-chlorophenyl)hydrazinyl)-N-isopentyl-N-methylacetamide

The preparation of title compound is carried out by General Method 2using 4-chlorophenyl hydrazine hydrochloride and2-bromo-N-isopentyl-N-methylacetamide.

Example 8 Preparation of 1-(4-chlorophenyl)-1-(prop-2-ynyl)hydrazine

The preparation of title compound is carried out by General Method 2using 4-chlorophenyl hydrazine hydrochloride and propargyl bromide.

Example 9 Preparation of 1-(4-chlorophenyl)-1-(3-phenylpropyl)hydrazine

The preparation of title compound is carried out by General Method 2using 4-chlorophenyl hydrazine hydrochloride and1-(3-bromopropyl)benzene.

Example 10 Preparation of2-(5-chloro-1-(2-(2-methylpyrimidin-5-yl)ethyl)-1H-indol-3-yl)-N-methylethanamine

The title compound is prepared by General Method 3 using1-(4-chlorophenyl)-1-(2-(2-methylpyrimidin-5-yl)ethyl)hydrazine and4,4-dimethoxy-N-methylbutan-1-amine.

Example 11 Preparation of2-(1-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5-methyl-1H-indol-3-yl)-N-methylethanamine

The title compound is prepared by General Method 10 using1-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1-p-tolylhydrazine (Example2) and 4,4-dimethoxy-N-methylbutan-1-amine.

Example 12 Preparation of2-(5-chloro-1-(2-(piperidin-1-yl)ethyl)-1H-indol-3-yl)-N-methylethanamine

The title compound is prepared by General Method 10 using1-(4-chlorophenyl)-1-(2-(piperidin-1-yl)ethyl)hydrazine (Example 3) and4,4-dimethoxy-N-methylbutan-1-amine.

Example 13 Preparation of2-(5-chloro-1-(2-cyclopentylethyl)-1H-indol-3-yl)-N-methylethanamine

The title compound is prepared by General Method 10 using1-(4-chlorophenyl)-1-(2-cyclopentylethyl)hydrazine (Example 4) and4,4-dimethoxy-N-methylbutan-1-amine.

Example 14 Preparation of2-(5-chloro-1-(2-(3,3-dimethylcyclopentyl)ethyl)-1H-indol-3-yl)-N-methylethanamine

The title compound is prepared by General Method 10 using1-(4-chlorophenyl)-1-(2-(3,3-dimethylcyclopentyl)ethyl)hydrazine(Example 5) and 4,4-dimethoxy-N-methylbutan-1-amine.

Example 15 Preparation of2-(5-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)-1-(4-methylpiperidin-1-yl)ethanone

The title compound is prepared by General Method 10 using2-(1-(4-chlorophenyl)hydrazinyl)-1-(4-methylpiperidin-1-yl)ethanone(Example 6) and 4,4-dimethoxy-N-methylbutan-1-amine.

Example 16 Preparation of2-(5-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)-N-isopentyl-N-methylacetamide

The title compound is prepared by General Method 10 using2-(1-(4-chlorophenyl)hydrazinyl)-N-isopentyl-N-methylacetamide (Example7) and 4,4-dimethoxy-N-methylbutan-1-amine.

Example 17 Preparation of2-(5-chloro-1-(prop-2-ynyl)-1H-indol-3-yl)-N-methylethanamine

The title compound is prepared by General Method 10 using1-(4-chlorophenyl)-1-(prop-2-ynyl)hydrazine (Example 8) and4,4-dimethoxy-N-methylbutan-1-amine.

Example 18 Preparation of2-(5-chloro-1-(3-phenylpropyl)-1H-indol-3-yl)-N-methylethanamine

The title compound is prepared by General Method 10 using1-(4-chlorophenyl)-1-(3-phenylpropyl)hydrazine (Example 9) and4,4-dimethoxy-N-methylbutan-1-amine.

Example 19a Preparation of2,3,4,9-tetrahydro-2,6-dimethyl-9-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[3,4-b]indole.(Compound 1, Scheme I)

The title compound was prepared by following General Methods 1, 3 and 4.

(A) 1-(2-(6-methylpyridin-3-yl)ethyl)-1-p-tolylhydrazine

The title compound was prepared by General Method 1. Triethylamine (13.0mL, 94.5 mmol) was added dropwise to p-tolylhydrazine hydrochloride (5.0g, 31.5 mmol) over a period of 5-10 min. The reaction mixture wasstirred for additional 10 min. 5-(2-bromoethyl)-2-methylpyridine (6.3 g,31.5 mmol) was added dropwise at 25° C. over a period of 10-15 min. Thereaction mixture was stirred at RT for 1 h and the subsequently heatedat 90° C. for 2-3 h at which point the reaction was found complete byTLC and LC-MS. Reaction mixture was concentrated under reduced pressureand diluted with water (50 mL) and extracted with ethyl acetate (100mL×2). The organic layer was separated, dried (Na₂SO₄) and concentratedto obtain crude product as dark brown oil (16.7 g). Purification ofcrude product by column chromatography (silica gel, 100-200 mesh,eluent: 0-40% ethyl acetate-Hexane) furnished 1.92 g of pure product asbrown liquid. Yield: 25%.

(B)N-methyl-2-(5-methyl-1-(2-(6-methylpyridin-3-yl)ethyl)-1H-indol-3-yl)ethanamine

The title compound was prepared by General Method 3.1-(2-(6-methylpyridin-3-yl)ethyl)-1-p-tolylhydrazine (250 mg) wassuspended in water (2 mL) and 28% aqueous HCl (0.135 mL) was added.4,4-diethoxy-N-methylbutan-1-amine (0.18 g) was added to the resultingsolution and the reaction mixture was heated to 60-80° C. and anadditional 28% HCl (0.135 mL) was added and the reaction mixture washeated for additional 3 h. The reaction mixture was concentrated underreduced pressure and the residue was purified by silica gelchromatography (eluent EtOAc/EtOH/NH₃: 7/3/1) to obtain the product.

(C)2,3,4,9-tetrahydro-2,6-dimethyl-9-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[3,4-b]indole(Compound 1)

The title compound was prepared by General Method 4. 150 mg ofN-methyl-2-(5-methyl-1-(2-(6-methylpyridin-3-yl)ethyl)-1H-indol-3-yl)ethanaminewas dissolved in acetonitrile (4 mL) containing 5% TFA and the reactionmixture was heated to reflux. 37% aqueous formaldehyde (0.04 mL) wasadded and the reflux was continued for additional 1.5 h. The reactionmixture was cooled to 25° C., concentrated under reduced pressure andpartitioned between ethyl acetate and satd. Aqueous NaHCO₃. The organiclayer was dried over sodium sulfate, evaporated under reduced pressureand the residue was purified by silica gel chromatography (eluentMethanol: aqueous NH₃, 95:5) to obtain the product. The free base wasconverted into its dihydrochloride salt by treatment of dioxane-HCl. ¹HNMR (DMSO) δ 11.7 (bs, 1H), 8.6 (s, 1H), 8.3 (d, 1H), 7.7 (d, 1H), 7.3(d, 1H), 7.25 (s, 1H), 6.9 (d, 1H), 4.8 (m, 1H), 4.4 (m, 1H), 4.35 (t,2H), 3.7 (bs, 1H), 3.55 (s, 3H), 3.5 (m, 1H), 3.4 (bs, 1H), 3.1 (t, 2H),3.05 (bs, 1H), 2.65 (3, 3H), 2.35 (s, 3H). MS m/z observed 320. HPLC RT3.63 min.

Example 19b Preparation of Compound 1

N-methyl-2-(5-methyl-1-(2-(6-methylpyridin-3-yl)ethyl)-1H-indol-3-yl)ethanamine(150 mg) was dissolved in acetonitrile (4 mL) containing 5% TFA and thereaction mixture was refluxed. 37% aqueous formaldehyde (0.04 mL) wasadded and the reaction mixture was refluxed for additional 1.5 h, cooledto 25° C., concentrated under reduced pressure and partitioned betweenethyl acetate and saturated aqueous NaHCO₃. The organic layer was driedover sodium sulfate, evaporated under reduced pressure and the residuewas purified by silica gel chromatography (eluent Methanol: aqueous NH₃,95:5) to obtain2,3,4,9-tetrahydro-2,6-dimethyl-9-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[3,4-b]indole.The free base was converted into its dihydrochloride salt by treatmentof dioxane-HCl. ¹H NMR (DMSO): 11.7 (bs, 1H), 8.6 (s, 1H), 8.3 (d, 1H),7.7 (d, 1H), 7.3 (d, 1H), 7.25 (s, 1H), 6.9 (d, 1H), 4.8 (m, 1H), 4.4(m, 1H), 4.35 (t, 2H), 3.7 (bs, 1H), 3.55 (s, 3H), 3.5 (m, 1H), 3.4 (bs,1H), 3.1 (t, 2H), 3.05 (bs, 1H), 2.65 (s, 3H), 2.35 (s, 3H).

Example 20a Preparation of9-(2-cyclohexylethyl)-2,3,4,9-tetrahydro-2,6-dimethyl-1H-pyrido[3,4-b]indole(Compound 2, Scheme I)

The title compound was prepared by following General Methods 2, 3 and 4.

(A) 1-(2-cyclohexylethyl)-1-p-tolylhydrazine

The title compound was prepared by General Method 2. p-tolylhydrazinehydrochloride (0.96 g, 6.0 mmol) was added to a vigorously stirredmixture of tetra-n-butylammonium chloride (84 mg, 0.3 mmol) in 50%aqueous sodium hydroxide (6 mL) followed by 2-cyclohexylethyl bromide(1.26 g, 6.6 mmol). The mixture was heated at 60° C. (oil bath temp.)for 6 h. After cooling to room temperature, water (20-30 mL) was addedand the mixture extracted with chloroform (3×10 mL). The total extractwas dried (sodium sulfate), evaporated in vacuo to give a dark oil (1.49g) which was chromatographed (45 g of silica gel, eluted withdichloromethane) to give the product as a yellow-orange oil (0.68 g,2.93 mmol, 48.8%).

(B) 2-(1-(2-cyclohexylethyl)-5-methyl-1H-indol-3-yl)-N-methylethanamine

The title compound was prepared by General Method 3. A solution of1-(2-cyclohexylethyl)-1-p-tolylhydrazine (0.15 g) in water (1 mL) andconc. HCl (0.18 mL) was heated to 60° C. EtOH (1 mL) was added followedby 4,4-diethoxy-N-methylbutan-1-amine (0.12 g) and the temperature wasraised to 90° C. Conc. HCl (0.1 mL) was added and the heating wascontinued for an additional 6 h after which the reaction mixture wascooled and stirred at 25° C. for 12 h. The reaction mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel chromatography (eluent EtOAc/EtOH/NH₃: 9/1/0.1) to obtain 79mg of product.

(C)9-(2-cyclohexylethyl)-2,3,4,9-tetrahydro-2,6-dimethyl-1H-pyrido[3,4-b]indole(Compound 2)

The title compound was prepared by General Method 4.2-(1-(2-cyclohexylethyl)-5-methyl-1H-indol-3-yl)-N-methylethanamine (72mg) was dissolved in acetonitrile (2 mL) containing 5% TFA and thereaction mixture was heated to reflux. 37% aqueous formaldehyde (0.02mL) was added and the reflux was continued for additional 2 h. Thereaction mixture was cooled to 25° C., concentrated under reducedpressure and partitioned between ethyl acetate and satd. Aqueous NaHCO₃.The organic layer was dried over sodium sulfate, evaporated underreduced pressure and the residue was purified by silica gelchromatography (eluent EtOAc/EtOH/NH₃: 9/1/0.1) to obtain 52 mg ofproduct. The free base was converted into its oxalate salt by treatmentof oxalic acid (1 equiv) in anhydrous THF. ¹H NMR (DMSO) δ 7.5 (d, 1H),7.4 (s, 1H), 6.9 (d, 1H), 4.3 (bs, 2H), 4.0 (t, 2H), 3.6 (bs, 2H), 2.8(m, 5H), 2.3 (s, 3H), 1.8-0.7 (m, 13H). MS m/z observed 311. HPLC RT5.93 min.

Example 20b Preparation of Compound 2

2-(1-(2-cyclohexylethyl)-5-methyl-1H-indol-3-yl)-N-methylethanamine (72mg, 0.23 mmol) was dissolved in acetonitrile (2 mL) containing 5% TFAand the reaction mixture was refluxed. 37% aqueous formaldehyde (0.02mL) was added to the reaction mixture and refluxed for additional 2 h,cooled to 25° C., concentrated under reduced pressure and partitionedbetween ethyl acetate and saturated aqueous NaHCO₃. The organic layerwas dried over sodium sulfate, evaporated under reduced pressure and theresidue was purified by silica gel chromatography (eluentEtOAc/EtOH/NH₃: 9/1/0.1) to obtain9-(2-cyclohexylethyl)-2,3,4,9-tetrahydro-2,6-dimethyl-1H-pyrido[3,4-b]indole(52 mg). The free base was converted into its oxalate salt by treatmentof oxalic acid (1 equiv) in anhydrous THF. ¹H NMR (DMSO): 7.5 (d, 1H),7.4 (s, 1H), 6.9 (d, 1H), 4.3 (bs, 2H), 4.0 (t, 2H), 3.6 (bs, 2H), 2.8(m, 5H), 2.3 (s, 3H), 1.8-0.7 (m, 13H).

Example 21a Preparation of9-(4-fluorophenethyl)-6-chloro-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole(Compound 3, Scheme I)

The title compound was prepared by following General Methods 2, 3 and 4.

(A) 1-(4-fluorophenethyl)-1-(4-chlorophenyl)hydrazine

The title compound was prepared by General Method 2.4-chlorophenylhydrazine hydrochloride (2.2 g) was added to a vigorouslystirred mixture of tetra-n-butylammonium chloride (200 mg) in 50%aqueous sodium hydroxide (12 mL) followed by 4-fluorophenethyl bromide(2.5 g). The mixture was heated at 75-80° C. (oil bath temp.) for 3.5 h.After cooling to room temperature, water was added and the mixtureextracted with chloroform and the chloroform layer was washed withbrine. The combined extract was dried (sodium sulfate), evaporated invacuo to give a dark oil which was chromatographed over silica gel,eluting with chloroform followed by recrystallization from cyclohexaneto obtain 750 mg of product.

(B) 2-(1-(4-fluorophenethyl)-5-chloro-1H-indol-3-yl)-N-methylethanamine

The title compound was prepared by General Method 3.1-(4-fluorophenethyl)-1-(4-chlorophenyl)hydrazine (500 mg) was convertedinto its hydrochloride salt by dissolving in ethyl acetate and treatmentof dioxane-HCl. The salt was dissolved in ethanol/water (1/1; 4 mL)) andwas heated to 60° C. 4,4-diethoxy-N-methylbutan-1-amine (0.35 g) wasadded and the temperature was raised to 70-80° C. 28% aqueous HCl (0.24mL) was added and the heating was continued for 40 min. Additionalamount of 4,4-diethoxy-N-methylbutan-1-amine (0.3 g) and % aqueous HCl(0.3 mL) was added and heating was continued for additional 3 h afterwhich the reaction mixture was cooled and stirred at 25° C. for 12 h.The reaction mixture was concentrated under reduced pressure and theresidue was purified by silica gel chromatography (eluentEtOAc/EtOH/NH3: 7/3/1) to obtain 600 mg of product.

(C)9-(4-fluorophenethyl)-6-chloro-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole(Compound 3)

The title compound was prepared by General Method 4.2-(1-(4-fluorophenethyl)-5-chloro-1H-indol-3-yl)-N-methylethanamine (600mg) was dissolved in acetonitrile (10 mL) containing 5% TFA and thereaction mixture was heated to reflux. 37% aqueous formaldehyde (0.17mL) was added and the reflux was continued for 15-20 min. The reactionmixture was cooled to 25° C., concentrated under reduced pressure andpartitioned between ethyl acetate and satd. Aqueous NaHCO₃. The organiclayer was dried over sodium sulfate, evaporated under reduced pressureand the residue was purified by silica gel chromatography (eluent 6%methanol-chloroform) to obtain 170 mg of product. The free base wasconverted into its HCl salt by treatment of HCL-ether. ¹H NMR (CDCl₃) δ13.1 (s, 1H), 7.25-7.1 (m, 3H), 6.8 (m, 2H), 6.7 (m, 2H), 4.4 (m, 1H),4.2 (m, 1H), 3.9 (m, 1H), 3.4 (m, 1H), 3.2-3.0 (m, 3H), 2.8 (m, 3H), 2.6(s, 3H). MS m/z observed 343. HPLC RT 5.16 min.

Example 21b Preparation of Compound 3

2-(1-(4-fluorophenethyl)-5-chloro-1H-indol-3-yl)-N-methylethanamine (600mg) was dissolved in acetonitrile (10 mL) containing 5% TFA and thereaction mixture was refluxed. 37% aqueous formaldehyde (0.17 mL) wasadded and the reaction mixture was refluxed for an additional for 15-20min, cooled to 25° C., concentrated under reduced pressure andpartitioned between ethyl acetate and saturated aqueous NaHCO₃. Theorganic layer was dried over sodium sulfate, evaporated under reducedpressure and the residue was purified by silica gel chromatography(eluent 6% methanol-chloroform) to yield the product (170 mg). The freebase was converted into its HCl salt by treatment of HCl-ether. ¹H NMR(CDCl₃): 13.1 (s, 1H), 7.25-7.1 (m, 3H), 6.8 (m, 2H), 6.7 (m, 2H), 4.4(m, 1H), 4.2 (m, 1H), 3.9 (m, 1H), 3.4 (m, 1H), 3.2-3.0 (m, 3H), 2.8 (m,3H), 2.6 (s, 3H).

Example 22 Preparation of6-chloro-2,3,4,9-tetrahydro-2-methyl-9-(2-(2-methylpyrimidin-5-yl)ethyl)-1H-pyrido[3,4-b]indole(Compound 4, Scheme I/II) Approach A.

The title compound is prepared by following General Methods 1, 3 and 4using 4-chlorophenylhydrazine hydrochloride,5-(2-bromoethyl)-2-methylpyrimidine, and triethylamine (General Method1), 3,1-(4-chlorophenyl)-1-(2-(2-methylpyrimidin-5-yl)ethyl)hydrazine(Example 1) and 4,4-diethoxy-N-methylbutan-1-amine (General Method 3)and2-(5-chloro-1-(2-(2-methylpyrimidin-5-yl)ethyl)-1H-indol-3-yl)-N-methylethanamine(Example 10), formaldehyde and TFA in acetonitrile (General Method 4).

Approach B

The title compound is prepared by following General Methods 3, 4 and 9by using 4-chlorophenylhydrazine hydrochloride and4,4-diethoxy-N-methylbutan-1-amine (General Method 3),2-(5-chloro-1H-indol-3-yl)-N-methylethanamine, formaldehyde and TFA inacetonitrile (General Method 4) and6-chloro-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole and2-methyl-5-vinylpyrimidine (General Method 9).

Example 23a Preparation of9-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,9-tetrahydro-2,6-dimethyl-1H-pyrido[3,4-b]indole(Compound 5, Scheme I/II) Approach A

The title compound is prepared by following General Methods 1, 3 and 4using p-tolylhydrazine hydrochloride,5-(2-bromoethyl)-2-(trifluoromethyl)pyridine, and triethylamine (GeneralMethod 1),1-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1-p-tolylhydrazine (Example2) and 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and2-(1-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5-methyl-1H-indol-3-yl)-N-methylethanamine(Example 11), formaldehyde and TFA in acetonitrile (General Method 4).

Approach B

The title compound is prepared by following General Methods 3, 4 and 9by using p-tolylhydrazine hydrochloride and4,4-diethoxy-N-methylbutan-1-amine (General Method 3),N-methyl-2-(5-methyl-1H-indol-3-yl)ethanamine, formaldehyde and TFA inacetonitrile (General Method 4) and2,3,4,9-tetrahydro-2,6-dimethyl-1H-pyrido[3,4-b]indole and2-(trifluoromethyl)-5-vinylpyridine (General Method 9).

Example 23b Preparation of Compound 5

A mixture of 2,6-dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (50 mg, 0.25mmol), 2-trifluoromethyl-5-vinyl pyridine (48 mg, 0.27 mmol) andpotassium hydroxide (49 mg, 0.87 mmol) in N-methyl-2-pyrrolidinone (0.3mL) was heated to 45° C. for 1 h. The reaction mixture was cooled; brine(2 mL) was added followed by extraction with ethyl acetate (3×5 mL). Thecombined organic layer was dried over MgSO₄, filtered and concentratedunder reduced pressure to obtain a brown oil which was purified bycolumn chromatography (silica gel, eluent: dichloromethane followed by2-8% methanol in dichloromethane) to yield a dark yellow semisolid (40mg). The semisolid was dissolved in dichloromethane (2 mL) and washedwith water (0.5 mL), filtered through a Varian drying tube and washedwith dichloromethane (3×2 mL). The combined organic phase wasconcentrated under reduced pressure to give a yellow solid (18.5 mg).The free base was converted to the hydrochloride by dissolving theproduct in methanol (4 mL) and 2M hydrochloride in diethyl ether (0.5mL) was added. The solution was concentrated under reduced pressure. Theresidue was triturated with diethyl ether and decanted (2×7 mL) and thesolvent removed under reduced pressure to yield9-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,9-tetrahydro-2,6-dimethyl-1H-pyrido[3,4-b]indole(17 mg, 15%). ¹H NMR (CD₃OD): 8.4 (s, 1H), 7.67-7.9 (m, 2H), 7.4 (s,1H), 7.2 (d, 1H), 7.0 (d, 1H) 4.5 (bs, 4H), 3.7 (bs, 2H), 3.1-3.3 (m,7H), 2.5 (s, 3H).

Example 24 Preparation of6-chloro-9-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole(Compound 6, Scheme I/II) Approach A

The title compound is prepared by following General Methods 1, 3 and 4using 4-chlorophenylhydrazine hydrochloride,5-(2-bromoethyl)-2-(trifluoromethyl)pyridine, and triethylamine (GeneralMethod 1),1-(4-chlorophenyl)-1-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)hydrazineand 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and2-(5-chloro-1-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-indol-3-yl)-N-methylethanamine,formaldehyde and TFA in acetonitrile (General Method 4).

Approach B

The title compound is prepared by following General Methods 3, 4 and 9by using 4-chlorophenylhydrazine hydrochloride and4,4-diethoxy-N-methylbutan-1-amine (General Method 3),2-(5-chloro-1H-indol-3-yl)-N-methylethanamine, formaldehyde and TFA inacetonitrile (General Method 4) and6-chloro-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole and2-(trifluoromethyl)-5-vinylpyridine (General Method 9).

Approach C

Method for the synthesis of compound 6[6-chloro-2-methyl-9-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole]:(4-chlorophenyl)hydrazine is reacted with4,4-dimethoxy-N-methylbutan-1-amine (Phytochemistry 1985, 24 (8),1653-1656) to generate 2-(5-chloro-1H-indol-3-yl)-N-methylethanaminewhich upon treatment with formaldehyde, under standard Pictet Spinglerreaction conditions (U.S. Pat. No. 2,642,438) gives6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. The furtherreaction of this unsubstituted β-carboline with2-(trifluoromethyl)-5-vinylpyridine gives the desired compound[6-chloro-2-methyl-9-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole],compound 6. After the successful synthesis of the compound, purificationcan be achieved using standard normal phase or reverse phase methods.

Example 25 Preparation of2-(7-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-1-(6-methylpyridin-3-yl)ethanol(Compound 7, Scheme III) Approach A

The title compound is prepared by following General Methods 3, 4 and 8by using 3-chlorophenylhydrazine hydrochloride and4,4-diethoxy-N-methylbutan-1-amine (General Method 3),2-(6-chloro-1H-indol-3-yl)-N-methylethanamine, formaldehyde and TFA inacetonitrile (General Method 4) and7-chloro-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole,2-methyl-5-(oxiran-2-yl)pyridine and NaH (General Method 8).

Approach B

Method for the preparation of compound 7[[2-(7-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-(6-methylpyridin-3-yl)ethanol]:(3-chlorophenyl)hydrazine is reacted with4,4-dimethoxy-N-methylbutan-1-amine (put in the references for this) togenerate 2-(6-chloro-1H-indol-3-yl)-N-methylethanamine, which upontreatment with formaldehyde, under standard Pictet Spingler reactionconditions (insert the reference for this) gives7-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. The furtherreaction of this unsubstituted β-carboline with2-methyl-5-(oxiran-2-yl)pyridine (carboline, aryl/heteroaryl oxide, NaH,DMF, 120° C.) gives the desired compound2-(7-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-(6-methylpyridin-3-yl)ethanol,compound 7. After the successful synthesis of the compound, purificationcan be achieved using standard normal phase or reverse phase methods.

Example 26 Preparation of6-aza-2,3,4,9-tetrahydro-2-methyl-9-(2-methyl-2-(6-methylpyridin-3-yl)propyl)-1H-pyrido[3,4-b]indole(Compound 8, Scheme I/II)

The title compound is prepared by following General Methods 1, 3 and 4by using 1-(pyridin-4-yl)hydrazine hydrochloride,5-(1-bromo-2-methylpropan-2-yl)-2-methylpyridine, and triethylamine(General Method 1),1-(2-methyl-2-(6-methylpyridin-3-yl)propyl)-1-(pyridin-4-yl)hydrazineand 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) andN-methyl-2-(1-(2-methyl-2-(6-methylpyridin-3-yl)propyl)-1H-pyrrolo[3,2-c]pyridin-3-yl)ethanamine,formaldehyde and TFA in acetonitrile (General Method 4)

Example 27 Preparation of5-aza-2,3,4,9-tetrahydro-2-methyl-9-(1-(6-methylpyridin-3-yl)propan-2-yl)-1H-pyrido[3,4-b]indole(Compound 9, Scheme I/II)

The title compound is prepared by following General Methods 3, 4 and 9by using 1-(pyridin-3-yl)hydrazine hydrochloride and4,4-diethoxy-N-methylbutan-1-amine (General Method 3),N-methyl-2-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethanamine, formaldehyde andTFA in acetonitrile (General Method 4) and5-aza-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole and2-methyl-5-(prop-1-enyl)pyridine (General Method 9).

Example 28 Preparation of6-chloro-9-((1-(4-fluorophenyl)cyclopropyl)methyl)-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole(Compound 10, Scheme I/II)

The title compound is prepared by following General Methods 1, 3 and 4by) using 4-chlorophenylhydrazine hydrochloride,1-(1-(bromomethyl)cyclopropyl)-4-fluorobenzene, and triethylamine(General Method 1),1-(4-chlorophenyl)-1-((1-(4-fluorophenyl)cyclopropyl)methyl)hydrazineand 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and2-(5-chloro-1-((1-(4-fluorophenyl)cyclopropyl)methyl)-1H-indol-3-yl)-N-methylethanamine,formaldehyde and TFA in acetonitrile (General Method 4).

Example 29 Preparation of6-chloro-9-(2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole(Compound 11, Scheme I/II) Approach A

The title compound is prepared by following General Methods 1, 3 and 4using 4-chlorophenylhydrazine hydrochloride,5-(2-bromoethyl)-2-(trifluoromethyl)pyrimidine, and triethylamine(General Method 1),1-(4-chlorophenyl)-1-(2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)hydrazineand 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and2-(5-chloro-1-(2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-1H-indol-3-yl)-N-methylethanamine,formaldehyde and TFA in acetonitrile (General Method 4).

Approach B

The title compound is prepared by following General Methods 3, 4 and 9by using 4-chlorophenylhydrazine hydrochloride and4,4-diethoxy-N-methylbutan-1-amine (General Method 3),2-(5-chloro-1H-indol-3-yl)-N-methylethanamine, formaldehyde and TFA inacetonitrile (General Method 4) and6-chloro-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole and2-(trifluoromethyl)-5-vinylpyrimidine (General Method 9).

Example 30 Preparation of5-aza-2,3,4,9-tetrahydro-2-methyl-9-(2-methyl-1-(6-methylpyridin-3-yl)propan-2-yl)-1H-pyrido[3,4-b]indole(Compound 12, Scheme I/II)

The title compound is prepared by following General Methods 3, 4 and 9by using 1-(pyridin-3-yl)hydrazine hydrochloride and4,4-diethoxy-N-methylbutan-1-amine (General Method 3),N-methyl-2-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethanamine, formaldehyde andTFA in acetonitrile (General Method 4) and5-aza-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole and2-methyl-5-(2-methylprop-1-enyl)pyridine (General Method 9).

Example 31 Preparation of2-(8-fluoro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-1-(6-methylpyridin-3-yl)ethanol(Compound 13, Scheme III)

The title compound is prepared by following General Methods 3, 4 and 8by using 2-fluorophenylhydrazine hydrochloride and4,4-diethoxy-N-methylbutan-1-amine (General Method 3),2-(7-fluoro-1H-indol-3-yl)-N-methylethanamine, formaldehyde and TFA inacetonitrile (General Method 4) and8-fluoro-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole,2-methyl-5-(oxiran-2-yl)pyridine and NaH (General Method 8).

Example 32a Preparation of2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-N-isopentyl-N-methylacetamide(Compound 14, Scheme IV)

Compound 14 was prepared according to a general method detailed herein.

Approach A

The title compound is prepared by following General Methods 1, 3, 4, 5and 7 by using 4-chlorophenylhydrazine hydrochloride, ethylbromoacetate, and triethylamine (General Method 1), ethyl2-(1-(4-chlorophenyl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(5-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate, formaldehydeand TFA in acetonitrile (General Method 4), ethyl2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetateand NaOH (General Method 5), and2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)aceticacid, N,3-dimethylbutan-1-amine and EDCI (General Method 7).

Approach B

Method for the preparation of compound 14[2-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-N-isopentyl-N-methylacetamide]:(4-chlorophenyl)hydrazine is alkylated with ethyl 2-bromoacetate to givethe substituted phenylhydrazine ethyl2-(1-(4-chlorophenyl)hydrazinyl)acetate (III). The reaction of III with4,4-dimethoxy-N-methylbutan-1-amine gives the indole derivative ethyl2-(5-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate (V).Effecting the indole to standard Pictet Spingler conditions withformaldehyde gives the β-carboline intermediate (VI) ethyl2-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetate.Following treatment of VI with base the acid (VIII)2-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)aceticacid is obtained. The treatment of this acid under standard peptidecoupling conditions with N,3-dimethylbutan-1-amine gives compound152-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-N-isopentyl-N-methylacetamide.After the successful synthesis of the compound, purification can beachieved using standard normal phase or reverse phase methods.

Example 32b Preparation of Compound 14

2-[5-Chloro-3-(2-methylamino-ethyl)-indol-1-yl]-N-methyl-N-(3-methyl-butyl)-acetamide(220 mg, 0.63 mmol) in 5% trifluoroacetic acid in acetonitrile (4 mL)was heated to 70° C. 37% aqueous formaldehyde (0.08 mL) was added to thereaction and refluxed for additional 30 min, cooled and concentratedunder reduced pressure. The resulting residue was dissolved inchloroform and washed with saturated aqueous sodium hydrogen carbonateand brine. The organic layer was dried (MgSO₄), filtered andconcentrated under reduced pressure to give a residue (120 mg). This waspurified using the Waters Preparative HPLC to yield the product (41.5mg, 28%). The free base was converted to the hydrochloride by dissolvingthe product in methanol (3 mL) and 2M hydrochloride in diethyl ether (1mL) was added. The solution was concentrated under reduced pressure. Theoil was triturated with diethyl ether and the solvent removed underreduced pressure to yield a buff solid (40 mg). ¹H NMR (CD₃OD): 7.6 (s,1H), 7.5 (d, 1H), 7.25 (d, 1H), 5.25 (bs, 2H), 4.5 (bs, 2H), 3.7 (m,2H), 3.6 (t, 2H), 3.5 (t, 2H), 3.4 (s, 3H), 3.2 (s, 3H), 1.7-1.5 (m,3H), 1.0 (d, 6H).

Example 33a Preparation of2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-N-(4-fluorophenyl)acetamide(Compound 15, Scheme IV)

The title compound is prepared by following General Methods 1, 3, 4, 5and 7 by using 4-chlorophenylhydrazine hydrochloride, ethylbromoacetate, and triethylamine (General Method 1), ethyl2-(1-(4-chlorophenyl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(5-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate, formaldehydeand TFA in acetonitrile (General Method 4), ethyl2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetateand NaOH (General Method 5), and2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)aceticacid, 4-fluoroaniline and EDCI (General Method 7).

Example 33b Preparation of Compound 15

2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)aceticacid (0.1 g, 0.39 mmol) was dissolved in dichloromethane (4 mL) and wascooled to 0° C., using an ice-bath; oxalyl chloride (0.04 mL, 0.43 mmol)was added drop-wise to the reaction mixture. Catalytic amount (1 drop)of dimethyl formamide was added and the reaction mixture was stirred for1 h at room temperature. Excess oxalyl chloride was distilled away underreduced pressure. A solution of 4-fluoroaniline (0.042 g, 0.43 mmol) indichloromethane (2 mL) and 4-dimethylaminopyridine (0.017 g, 0.143 mmol)was added to the residue under nitrogen at room temperature and thereaction mass was stirred for 30 min. The reaction mixture was quenchedwith water and neutralized with 10% NaHCO₃, extracted withdichloromethane (2×10 mL). The combined organic layer was dried oversodium sulfate and concentrated by rotary evaporation to obtain2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-N-(4-fluorophenyl)acetamide(6 mg) after purification by reverse-phase chromatography (C-18, 500mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection volume 5mL). ¹H NMR (DMSO): 11.4 (s, 1H), 10.6 (s, 1H), 7.6 (m, 3H), 7.4 (d,1H), 7.3-7.1 (m, 3H), 5.1 and 4.9 (d, 2H), 4.4 (q, 2H), 4.1-3.9 (bs,2H), 3.5 (s, 3H), 3.2-3.1 (m, 2H).

Example 34a Preparation of2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-N,N-dimethylacetamide(Compound 16, Scheme IV)

The title compound is prepared by following General Methods 1, 3, 4, 5and 7 by using 4-chlorophenylhydrazine hydrochloride, ethylbromoacetate, and triethylamine (General Method 1), ethyl2-(1-(4-chlorophenyl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(5-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate, formaldehydeand TFA in acetonitrile (General Method 4), ethyl2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetateand NaOH (General Method 5), and2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)aceticacid, N,N-dimethylamine and EDCI (General Method 7).

Example 34b Preparation of Compound 16

6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (100 mg, 0.5mmol), was dissolved in N,N-dimethylformamide. CuI (0.009 g, 0.05 mmol),L-proline (0.011 g, 0.091 mmol) and K₃PO₄ (0.194 g, 0.91 mmol) was addedto the solution and stirred for 10 min. at room temperature, followed bydrop-wise addition of 2-chloro-N,N-dimethylacetamide (0.066 g, 0.55mmol) and stirred at 90° C. for 12 h. After completion of the reaction,the reaction mixture was filtered through Celite, N,N-dimethylformamidewas evaporated under reduced pressure and extracted with ethyl acetate.The combined organic layer was dried over Na₂SO₄, and concentrated underreduced pressure to yield2-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-N,N-dimethylacetamideas TFA salt (9 mg) after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection volume 5mL). ¹H NMR (CD₃OD): 10.9 (bs, 1H), 7.65 (s, 1H), 7.38 (d, 1H), 7.19 (d,1H), 5.1-5.2 (m, 2H), 4.55 (s, 2H), 4.2-4.3 (m, 2H), 3.83-4.1 (m, 2H),3.25 (s, 3H), 3.19-3.25 (m, 3H), 3.0 (s, 3H).

Example 35a Preparation of2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-N-cyclohexylacetamide(Compound 17, Scheme IV)

The title compound is prepared by following General Methods 1, 3, 4, 5and 7 by using 4-chlorophenylhydrazine hydrochloride, ethylbromoacetate, and triethylamine (General Method 1), ethyl2-(1-(4-chlorophenyl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(5-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate, formaldehydeand TFA in acetonitrile (General Method 4), ethyl2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetateand NaOH (General Method 5), and2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)aceticacid, cyclohexaneamine and EDCI (General Method 7).

Example 35b Preparation of Compound 17

6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (100 mg, 0.5mmol), was dissolved in N,N-dimethylformamide. CuI (0.009 g, 0.05 mmol),L-proline (0.011 g, 0.091 mmol) and K₃PO₄ (0.194 g, 0.91 mmol) was addedto the solution and stirred for 10 min. at room temperature, followed bydrop-wise addition of 2-chloro-N-cyclohexylacetamide (0.096 g, 0.55mmol) and stirred at 90° C. for 12 h. After completion of the reaction,the reaction mixture filtered through Celite, N,N-dimethylformamide wasevaporated under reduced pressure and extracted with ethyl acetate. Thecombined organic layer was dried over Na₂SO₄, and concentrated underreduced pressure to yield2-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-N-cyclohexylacetamide)as TFA salt (40 mg) after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection volume 5mL). ¹H NMR (DMSO-D6): 11.25 (bs, 1H), 8.43 (bs, 1H), 7.6 (s, 1H), 7.41(d, 1H), 7.18 (d, 1H), 4.8-5.9 (m, 2H), 4.1-4.2 (m, 2H), 3.82-3.0 (m,2H), 3.25 (s, 3H), 2.92-3.2 (m, 3H), 1.5-1.8 (m, 6H), 1.15-1.29 (m, 4H).

Example 36a Preparation of2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-N-cyclohexyl-N-methylacetamide(Compound 18, Scheme IV)

The title compound is prepared by following General Methods 1, 3, 4, 5and 7 by using 4-chlorophenylhydrazine hydrochloride, ethylbromoacetate, and triethylamine (General Method 1), ethyl2-(1-(4-chlorophenyl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(5-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate, formaldehydeand TFA in acetonitrile (General Method 4), ethyl2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetateand NaOH (General Method 5), and2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)aceticacid, N-methylcyclohexylamine and EDCI (General Method 7).

Example 36b Preparation of Compound 18

2-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)aceticacid (50 mg, 0.18 mmol) was dissolved in dichloromethane (3 mL) andcooled to 0° C. Oxalyl chloride (0.027 g, 0.22 mmol) was added drop-wisefollowed by catalytic amount of N,N-dimethylformamide, and the reactionmixture was stirred at RT for 1 h. Oxalyl chloride was evaporated underreduced pressure to obtain the corresponding acid chloride. A solutionof N-methylcyclohexanamine (0.025 g, 0.22 mmol) and4-dimethylaminopyridine (26 mg, 0.22 mmol) in dichloromethane(previously stirred at RT for 1 h) was added drop-wise to the acidchloride. The progress of the reaction was monitored by LCMS. Aftercompletion of the reaction, the reaction mixture was quenched with icewater and extracted with dichloromethane. The organic layer was driedover anhydrous sodium sulfate, evaporated under reduced pressure andpurified by reverse phase chromatography to yield2-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-N-cyclohexyl-N-methylacetamideas TFA salt (2.4 mg). ¹H NMR (DMSO): 7.6 (s, 1H), 7.4 (d, 1H), 7.15 (d,1H), 5.15 (d, 1H), 4.95 (d, 1H), 4.65 (s, 1H), 4.50 (s, 1H), 4.3 (m,1H), 4.1 (m, 1H), 3.9 (m, 1H), 3.1 (m, 2H), 3.35 (s, 3H), 2.8 (s, 3H),1.9-1.1 (m, 10H).

Example 37 Preparation of isopentyl2-(1,2,3,4-tetrahydro-2,6-dimethylpyrido[3,4-b]indol-9-yl)acetate(Compound 19, Scheme V) Approach A

The title compound is prepared by following General Methods 1, 3, 4, 5and 6 by using p-tolylhydrazine hydrochloride, ethyl bromoacetate, andtriethylamine (General Method 1), ethyl2-(1-(4-methylphenyl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(5-methyl-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate, formaldehydeand TFA in acetonitrile (General Method 4), ethyl2-(6-methyl-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetateand NaOH (General Method 5), and2-(6-methyl-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)aceticacid, 3-methylbutan-1-ol and EDCI (General Method 6).

Approach B

Method for the preparation of compound 19 [isopentyl2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetate]:p-tolylhydrazine is alkylated with ethyl 2-bromoacetate to give thesubstituted phenylhydrazine, ethyl 2-(1-p-tolylhydrazinyl)acetate (III).The reaction of III with 4,4-dimethoxy-N-methylbutan-1-amine gives theindole derivative ethyl2-(5-methyl-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate (V).Effecting the indole to standard Pictet Spingler conditions withformaldehyde gives the 1-carboline intermediate (VI) ethyl2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetate.Following treatment of VI with base the acid (VIII)2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetic acidis obtained. The treatment of this acid with DCC or other standardcoupling reagents with 3-methylbutan-1-ol gives compound 19 isopentyl2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetate.After the successful synthesis of the compound, purification can beachieved using standard normal phase or reverse phase methods.

Example 38 Preparation of 4-fluorophenyl2-(1,2,3,4-tetrahydro-2,6-dimethylpyrido[3,4-b]indol-9-yl)acetate(Compound 20, Scheme V)

The title compound is prepared by following General Methods 1, 3, 4, 5and 6 by using p-tolylhydrazine hydrochloride, ethyl bromoacetate, andtriethylamine (General Method 1), ethyl2-(1-(4-methylphenyl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(5-methyl-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate, formaldehydeand TFA in acetonitrile (General Method 4), ethyl2-(6-methyl-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetateand NaOH (General Method 5), and2-(6-methyl-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)aceticacid, 4-fluorophenol and EDCI (General Method 6).

Example 39a Preparation of methyl2-(1,2,3,4-tetrahydro-2,6-dimethylpyrido[3,4-b]indol-9-yl)acetate(Compound 21, Scheme V)

The title compound is prepared by following General Methods 1, 3, and 4by using p-tolylhydrazine hydrochloride, methyl bromoacetate, andtriethylamine (General Method 1), methyl2-(1-(4-methylphenyl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), and methyl2-(5-methyl-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate, formaldehydeand TFA in acetonitrile (General Method 4).

Example 39b Preparation of Compound 21

2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetic acid(50 mg, 0.19 mmol) was dissolved in dichloromethane (3 mL) and cooled to0° C. Oxalyl chloride (0.03 mL, 0.23 mmol) was added drop-wise followedby catalytic amount of N,N-dimethylformamide, and the reaction mixturewas stirred at RT for 1 h. Oxalyl chloride was evaporated under reducedpressure to obtain the corresponding acid chloride. A solution ofisoamyl alcohol (0.02 g, 0.23 mmol) and 4-dimethylaminopyridine (26 mg,0.21 mmol) in dichloromethane (previously stirred at RT for 1 h) wasadded drop-wise to the acid chloride. The progress of the reaction wasmonitored by LCMS. After completion of the reaction, the reactionmixture was quenched with ice water and extracted with dichloromethane.The organic layer was washed with aq. sodium bicarbonate solution,dilute HCl solution, dried over anhydrous sodium sulfate, evaporatedunder reduced pressure and purified by reverse phase chromatography toyield methyl2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetate asTFA salt (2 mg). ¹H NMR (CD₃OD): 7.3 (s, 1H), 7.2 (d, 1H), 7.0 (d, 1H),5.0 (m, 2H), 4.5 (s, 2H), 4.1 (m, 1H), 3.9 (m, 1H), 3.8 (s, 3H), 3.5 (s,3H), 3.2 (m, 2H), 2.5 (s, 3H).

Example 40 Preparation of cyclohexyl2-(1,2,3,4-tetrahydro-2,6-dimethylpyrido[3,4-b]indol-9-yl)acetate(Compound 22, Scheme V)

The title compound is prepared by following General Methods 1, 3, 4, 5and 6 by using p-tolylhydrazine hydrochloride, ethyl bromoacetate, andtriethylamine (General Method 1), ethyl2-(1-(4-methylphenyl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(5-methyl-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate, formaldehydeand TFA in acetonitrile (General Method 4), ethyl2-(6-methyl-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetateand NaOH (General Method 5), and2-(6-methyl-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)aceticacid, cyclohexanol and EDCI (General Method 6).

Example 41 Preparation of isopropyl2-(1,2,3,4-tetrahydro-2,6-dimethylpyrido[3,4-b]indol-9-yl)acetate(Compound 23, Scheme V)

The title compound is prepared by following General Methods 1, 3, 4, 5and 6 by using p-tolylhydrazine hydrochloride, ethyl bromoacetate, andtriethylamine (General Method 1), ethyl2-(1-(4-methylphenyl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(5-methyl-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate, formaldehydeand TFA in acetonitrile (General Method 4), ethyl2-(6-methyl-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetateand NaOH (General Method 5), and2-(6-methyl-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)aceticacid, isopropanol and EDCI (General Method 6).

Example 42 Preparation of2-(7-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-N-isopentyl-N-methylacetamide(Compound 24, Scheme IV)

The title compound is prepared by following General Methods 1, 3, 4, 5and 7 by using 3-chlorophenylhydrazine hydrochloride, ethylbromoacetate, and triethylamine (General Method 1), ethyl2-(1-(3-chlorophenyl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(6-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate, formaldehydeand TFA in acetonitrile (General Method 4), ethyl2-(7-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetateand NaOH (General Method 5), and2-(7-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)aceticacid, N,3-dimethylbutan-1-amine and EDCI (General Method 7).

Example 43 Preparation of2-(5-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-N-(4-fluorophenyl)acetamide(Compound 25, Scheme IV)

The title compound is prepared by following General Methods 1, 3, 4, 5and 7 by using 3-chlorophenylhydrazine hydrochloride, ethylbromoacetate, and triethylamine (General Method 1), ethyl2-(1-(3-chlorophenyl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(4-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate, formaldehydeand TFA in acetonitrile (General Method 4), ethyl2-(5-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetateand NaOH (General Method 5), and2-(5-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)aceticacid, 4-fluoroaniline and EDCI (General Method 7).

Example 44 Preparation of cyclohexyl7-aza-2-(1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetate(Compound 26, Scheme V)

The title compound is prepared by following General Methods 1, 3, 4, 5and 6 by using 1-(pyridin-3-yl)hydrazine hydrochloride and ethylbromoacetate (General Method 1), ethyl2-(1-(pyridin-3-yl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(3-(2-(methylamino)ethyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)acetate,formaldehyde and TFA in acetonitrile (General Method 4), ethyl7-aza-2-(1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetate andNaOH (General Method 5), and7-aza-2-(1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetic acid,cyclohexanol and EDCI (General Method 6).

Example 45 Preparation of isopropyl8-aza-2-(1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetate(Compound 27, Scheme V)

The title compound is prepared by following General Methods 1, 3, 4, 5and 6 by using 1-(pyridin-2-yl)hydrazine hydrochloride and ethylbromoacetate (General Method 1), ethyl2-(1-(pyridin-2-yl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(3-(2-(methylamino)ethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)acetate,formaldehyde and TFA in acetonitrile (General Method 4), ethyl8-aza-2-(1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetate andNaOH (General Method 5), and8-aza-2-(1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetic acid,isopropanol and EDCI (General Method 6).

Example 46 Preparation of5-aza-N-cyclohexyl-2-(1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-N-methylacetamide(Compound 28, Scheme IV)

The title compound is prepared by following General Methods 1, 3, 4, 5and 7 by using 1-(pyridin-3-yl)hydrazine hydrochloride and ethylbromoacetate (General Method 1), ethyl2-(1-(pyridin-3-yl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(3-(2-(methylamino)ethyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)acetate,formaldehyde and TFA in acetonitrile (General Method 4), ethyl5-aza-2-(1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetate andNaOH (General Method 5), and5-aza-2-(1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetic acid,N-methylcyclohexylamine and EDCI (General Method 7).

Example 47a Preparation of6-chloro-2,3,4,9-tetrahydro-2-methyl-9-(3-phenylpropyl)-1H-pyrido[3,4-b]indole(Compound 29, Scheme I)

The title compound was prepared by following General Methods 2, 3 and 4using 4-chlorophenylhydrazine hydrochloride, 1-(3-bromopropyl)benzene,and tetra-n-butylammonium chloride (General Method 2),1-(4-chlorophenyl)-1-(3-phenylpropyl)hydrazine (Example 9) and4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and2-(5-chloro-1-(3-phenylpropyl)-1H-indol-3-yl)-N-methylethanamine(Example 18), formaldehyde and TFA in acetonitrile (General Method 4).

(A) N-(4-Chloro-phenyl)-N-(3-phenyl-propyl)-hydrazine

4-Chlorophenylhydrazine hydrochloride (550 mg, 3 mmol) was added to avigorously stirred mixture of tetra-n-butylammonium chloride (42 mg,0.15 mmol) in 50% aqueous sodium hydroxide (3 mL) followed by1-bromo-3-phenylpropane (670 mg, 3.3 mmol). The reaction was heated to60° C. (oil bath temperature) for 6 h. The reaction was cooled anddiluted with water (30 mL) and extracted with chloroform (3×10 mL). Thecombined organic layer was dried (Na₂SO₄), filtered and concentratedunder reduced pressure to a dark red oil (690 mg). The oil was subjectedto column chromatography (silica gel, eluent: 50% dichloromethane inhexane followed by 100% dichloromethane) to give a dark yellow oil (154mg, 20%).

(B) {2-[5-Chloro-1-(3-phenyl-propyl)-1H-indol-3-yl]-ethyl}-methyl-amine

28% aqueous HCl (0.07 mL, 0.54 mmol) was added to a solution ofN-(4-Chloro-phenyl)-N-(3-phenyl-propyl)-hydrazine (261 mg, 1 mmol) inethanol (1 mL) and water (0.5 mL) under a nitrogen atmosphere. Thereaction was heated to 60° C. (oil bath temperature) and4,4-diethoxy-N-methylbutan-1-amine (175 mg, 1 mmol) was added. Thereaction was heated to 90° C. and 28% aqueous HCl (0.08 mL, 0.61 mmol)was added. The reaction was heated at reflux for 6 h. More 4,4-diethoxy-N-methylbutan-1-amine (90 mg, 0.51 mmol) was added at 60° C.and more 28% aqueous HCl (0.19 mL, 1.46 mmol) was added at 90° C. Thereaction was heated to reflux for a further 8 h. The reaction was cooledand concentrated under reduced pressure. The red-brown residue wassubjected to column chromatography (silica gel, eluent: EtOAc followedby EtOAc:EtOH:NH₄OH 90:10:1) to give a brown oil (243 mg, 74%).

(C)6-chloro-2,3,4,9-tetrahydro-2-methyl-9-(3-phenylpropyl)-1H-pyrido[3,4-b]indole

37% aqueous formaldehyde (59 mg, 0.73 mmol) in acetonitrile (1 mL) wasadded to a refluxing solution of2-[5-Chloro-1-(3-phenyl-propyl)-1H-indol-3-yl]-ethyl}-methyl-amine (216mg, 0.66 mmol) in 5% trifluoroacetic acid in acetonitrile (6.6 mL) undera nitrogen atmosphere. The reaction was refluxed for 2 h. The reactionwas cooled and concentrated under reduced pressure. The resulting darkred residue was azeotroped with heptane, then dissolved in ethyl acetate(50 mL) and washed with saturated aqueous sodium hydrogen carbonate (10mL). The organic layer was dried (Na₂SO₄), filtered and concentratedunder reduced pressure to a dark brown gum (220 mg). The gum waspurified by column chromatography (silica gel, eluent: EtOAc followed byEtOAc:EtOH:NH₄OH 98:2:0.2) to give a brown oil (136 mg, 61%). The freebase was converted to the hydrochloride by dissolving the solid inanhydrous diethyl ether (˜30 mL) under a nitrogen atmosphere andfiltering, 2M hydrochloride in diethyl ether (0.25 mL, 0.5 mmol) wasadded to the filtrate under a nitrogen atmosphere to form a precipitate.The solvent was removed under reduced pressure. The residue wastriturated with anhydrous diethyl ether which was removed under areduced pressure to give the resulting hydrochloride (151 mg, 100%) as apink-buff solid.

Example 47b Preparation of Compound 29

37% aqueous formaldehyde (59 mg, 0.73 mmol) in acetonitrile (1 mL) wasadded to a refluxing solution of2-[5-Chloro-1-(3-phenyl-propyl)-1H-indol-3-yl]-ethyl}-methyl-amine (216mg, 0.66 mmol) in 5% trifluoroacetic acid in acetonitrile (6.6 mL) undera nitrogen atmosphere and refluxed for an additional 2 h. The reactionwas cooled and concentrated under reduced pressure. The resulting darkred residue was azeotroped with heptane, dissolved in ethyl acetate (50mL) and washed with saturated aqueous sodium hydrogen carbonate (10 mL).The organic layer was dried (Na₂SO₄), filtered and concentrated underreduced pressure to a dark brown gum (220 mg). The gum was purified bycolumn chromatography (silica gel, eluent: EtOAc followed by EtOAc:EtOH: NH₄OH 98:2:0.2) to yield a brown oil (136 mg, 61%). The free basewas converted to the hydrochloride by dissolving the solid in anhydrousdiethyl ether (˜30 mL) under a nitrogen atmosphere and filtering. 2 MHCl solution in diethyl ether (0.25 mL, 0.5 mmol) was added to thefiltrate under a nitrogen atmosphere to form a precipitate. The solventwas removed under reduced pressure. The residue was triturated withanhydrous diethyl ether which was removed under a reduced pressure toyield the resulting hydrochloride (151 mg, 100%) as a pink-buff solid.¹H NMR (DMSO): 11.4 (bs, 1H), 7.6 (s, 1H), 7.5 (d, 1H), 7.15-7.45 (m,6H), 4.7-4.6 (bs, 1H), 4.4-4.3 (bs, 1H), 4.1 (m, 2H), 3.7 (bs, 1H), 3.3(bs, 1H), 3.1-3.0 (m, 2H), 2.9 (s, 3H), 2.6 (t, 2H), 2.0 (t, 2H).

Example 48 Preparation of6-chloro-2,3,4,9-tetrahydro-2-methyl-9-(3-(pyridin-3-yl)propyl)-1H-pyrido[3,4-b]indole(Compound 30, Scheme I)

The title compound is prepared by following General Methods 1, 3 and 4using 4-chlorophenylhydrazine hydrochloride, 3-(3-bromopropyl)pyridine,and triethylamine (General Method 1),1-(4-chlorophenyl)-1-(3-(pyridin-3-yl)propyl)hydrazine and4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and2-(5-chloro-1-(3-(pyridin-3-yl)propyl)-1H-indol-3-yl)-N-methylethanamine,formaldehyde and TFA in acetonitrile (General Method 4).

Example 49 Preparation of6-chloro-9-(3-(4-fluorophenyl)propyl)-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole(Compound 31, Scheme I)

The title compound is prepared by following General Methods 1, 3 and 4using 4-chlorophenylhydrazine hydrochloride,1-(3-bromopropyl)-4-fluorobenzene, and triethylamine (General Method 1),1-(4-chlorophenyl)-1-(3-(4-fluorophenyl)propyl)hydrazine and4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and2-(5-chloro-1-(3-(4-fluorophenyl)propyl)-1H-indol-3-yl)-N-methylethanamine,formaldehyde and TFA in acetonitrile (General Method 4).

Example 50 Preparation of6-chloro-9-(3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole(Compound 32, Scheme I)

The title compound is prepared by following General Methods 1, 3 and 4using 4-chlorophenylhydrazine hydrochloride,5-(3-bromopropyl)-2-(trifluoromethyl)pyridine, and triethylamine(General Method 1),1-(4-chlorophenyl)-1-(3-(6-(trifluoromethyl)pyridin-3-yl)propyl)hydrazineand 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and2-(5-chloro-1-(3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-1H-indol-3-yl)-N-methylethanamine,formaldehyde and TFA in acetonitrile (General Method 4).

Example 51 Preparation of2,3,4,9-tetrahydro-2,6-dimethyl-9-(3-(6-methylpyridin-3-yl)propyl)-1H-pyrido[3,4-b]indole(Compound 33, Scheme I)

The title compound is prepared by following General Methods 1, 3 and 4using 4-chlorophenylhydrazine hydrochloride,5-(3-bromopropyl)-2-methylpyridine, and triethylamine (General Method1), 1-(3-(6-methylpyridin-3-yl)propyl)-1-p-tolylhydrazine and4,4-diethoxy-N-methylbutan-1-amine (General Method 3) andN-methyl-2-(5-methyl-1-(3-(6-methylpyridin-3-yl)propyl)-1H-indol-3-yl)ethanamine,formaldehyde and TFA in acetonitrile (General Method 4).

Example 52a Preparation of6-chloro-2,3,4,9-tetrahydro-2-methyl-9-(2-(piperidin-1-yl)ethyl)-1H-pyrido[3,4-b]indole(Compound 34, Scheme I)

The title compound was prepared by following General Methods 2, 3 and 4using 4-chlorophenylhydrazine hydrochloride, 1-(2-chloroethyl)piperidinehydrochloride, and tetra-n-butylammonium chloride (General Method 2),1-(4-chlorophenyl)-1-(2-(piperidin-1-yl)ethyl)hydrazine (Example 3) and4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and2-(5-chloro-1-(2-(piperidin-1-yl)ethyl)-1H-indol-3-yl)-N-methylethanamine(Example 12), formaldehyde and TFA in acetonitrile (General Method 4).

(A) N-(4-Chloro-phenyl)-N-(2-piperidin-1-yl-ethyl)-hydrazine

1-(2-Chloro-ethyl)piperidine (5 g, 27.9 mmol) was added to a vigorouslystirred mixture of 4-chlorophenyl hydrazine hydrochloride (5 g, 27.9mmol) and tetra-n-butylammonium chloride (0.40 g) in 50% aqueous sodiumhydroxide (30 mL). The reaction was heated to 80° C. (oil bathtemperature) for 3.5 h. The reaction was cooled, diluted with water andextracted with chloroform. The organic layer was washed with brine,dried (MgSO₄), filtered and concentrated under reduced pressure to givea red oil. The oil was subjected to column chromatography (silica gel,eluent: 10% methanol in chloroform) to give a red oil (˜3 g). This waspurified again by column chromatography (silica gel, eluent: 510%methanol in chloroform) to give a red oil (1.77 g, 25%).

(B){2-[5-Chloro-1-(2-piperidin-1-yl-ethyl)-1H-indol-3-yl]-ethyl}-methyl-amine

N-(4-Chloro-phenyl)-N-(2-piperidin-1-yl-ethyl)-hydrazine (1 g, 3.94mmol) was dissolved in ethyl acetate (3 mL) and 4M hydrochloride indioxane (23 equiv) was added. The mixture was concentrated under reducedpressure to a brown foam. This was dissolved in a mixture of ethanol (2mL) and water (4 mL) and heated to 70° C. The4,4-diethoxy-N-methylbutan-1-amine (0.67 g, 3.94 mmol) was added andthen heated to 8090° C. 28% aqueous HCl (0.51 mL, 3.94 mmol) was addedand the reaction heated at 80° C. for 4 h. The reaction was concentratedunder reduced pressure. The residue was subjected to columnchromatography (silica gel, eluent: EtOAc:EtOH:NH₄OH 7:3:1) to give aresidue (0.80 g). The residue was subjected to column chromatography(silica gel, eluent: EtOAc:EtOH:NH₄OH 7:3:1) to give a red oil (0.440g). The red oil was purified again by column chromatography (silica gel,eluent: EtOAc:EtOH:NH₄OH 7:3:1) to give the product (0.30 g, 23%).

(C)6-chloro-2,3,4,9-tetrahydro-2-methyl-9-(2-(piperidin-1-yl)ethyl)-1H-pyrido[3,4-b]indole

{2-[5-Chloro-1-(2-piperidin-1-yl-ethyl)-1H-indol-3-yl]-ethyl}-methyl-amine(0.30 g, 0.93 mmol) in 5% trifluoroacetic acid in acetonitrile (4 mL)was heated to reflux. 37% aqueous formaldehyde (0.1 mL) was added. Thereaction was refluxed for 1 h. The reaction was cooled and concentratedunder reduced pressure. The resulting oil was dissolved in ethyl acetateand washed with saturated aqueous sodium hydrogen carbonate and brine.The organic layer was dried (MgSO₄), filtered and concentrated underreduced pressure to a brown oily solid. The solid was purified by columnchromatography (silica gel, eluent: 10% methanol in chloroform) to givethe product (0.08 g, 25%). The free base was converted to thehydrochloride by dissolving the product in ethanol (2 mL) and 2Mhydrochloride in diethyl ether was added. The solution was concentratedunder reduced pressure to an oil. The oil was dissolved in chloroformand a few drops of methanol. The solution was concentrated under reducedpressure to give a solid (0.1 g) as the dihydrochloride salt.

Example 52b Preparation of Compound 34

{2-[5-Chloro-1-(2-piperidin-1-yl-ethyl)-1H-indol-3-yl]-ethyl}-methyl-amine(0.30 g, 0.93 mmol) in 5% trifluoroacetic acid in acetonitrile (4 mL)was refluxed. 37% aqueous formaldehyde (0.1 mL) was added to thereaction mixture and refluxed for an additional 1 h, cooled andconcentrated under reduced pressure. The resulting oil was dissolved inethyl acetate and washed with saturated sodium hydrogen carbonate andbrine solution. The organic layer was dried (MgSO₄), filtered andconcentrated under reduced pressure to obtain a brown oily solid. Thesolid was purified by column chromatography (silica gel, eluent: 10%methanol in chloroform) to give the product (0.08 g, 25%). The free basewas converted to the hydrochloride by dissolving the product in ethanol(2 mL) and 2M hydrochloride in diethyl ether was added. The solution wasconcentrated under reduced pressure to oil. The oil was dissolved inchloroform and a few drops of methanol and concentrated under reducedpressure to yield a solid (0.1 g) as the dihydrochloride salt. ¹H NMR(CD₃OD): 7.5 (d, 2H), 7.2 (d, 1H), 4.9 (d, 1H), 4.5 (m, 3H), 3.8 (bs,1H), 3.5-3.3 (bs, 5H), 3.4 (s, 3H), 3.0 (m, 4H), 1.8 (m, 5H), 1.5 (m,1H).

Example 53a Preparation of6-chloro-9-(2-cyclopentylethyl)-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole(Compound 35, Scheme I)

The title compound was prepared by following General Methods 2, 3 and 4using 4-chlorophenylhydrazine hydrochloride, (2-bromoethyl)cyclopentane,and tetra-n-butylammonium chloride (General Method 2),1-(4-chlorophenyl)-1-(2-cyclopentylethyl)hydrazine (Example 4) and4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and2-(5-chloro-1-(2-cyclopentylethyl)-1H-indol-3-yl)-N-methylethanamine(Example 13), formaldehyde and TFA in acetonitrile (General Method 4).

(A) N-(4-Chloro-phenyl)-N-(2-cyclopentyl-ethyl)-hydrazine

4-Chlorophenylhydrazine hydrochloride (1.65 g, 9 mmol) was added to avigorously stirred mixture of tetra-n-butylammonium chloride (0.126 g,0.45 mmol) in 50% aqueous sodium hydroxide (9 mL) followed by(2-bromo-ethyl)-cyclopentane (1.74 g, 9.9 mmol). The reaction was heatedto 60° C. (oil bath temperature) for 8 h. The reaction was cooled,diluted with water (75 mL) and extracted with chloroform (3×30 mL). Thecombined organic layer was dried (Na₂SO₄), filtered and concentratedunder reduced pressure to an orange oil (0.69 g). The oil was subjectedto column chromatography (silica gel, eluent: 50% dichloromethane inhexane followed by 70% dichloromethane in hexane) to give a yellow oil(1.17 g, 55%).

(B){2-[5-Chloro-1-(2-cyclopentyl-ethyl)-1H-indol-3-yl]-ethyl}-methyl-amine

28% aqueous HCl (0.3 mL, 2.26 mmol) was added to a solution ofN-(4-Chloro-phenyl)-N-(2-cyclopentyl-ethyl)-hydrazine (0.54 g, 2.26mmol) in ethanol (2.5 mL) and water (1 mL) under a nitrogen atmosphere.The reaction was heated to 60° C. (oil bath temperature) and4,4-diethoxy-N-methylbutan-1-amine (0.32 g, 1.84 mmol) was added. Thereaction was heated to reflux and 28% aqueous HCl (0.15 mL, 1.13 mmol)was added. The reaction was heated at reflux for 2.5 h. The reaction wascooled to 60° C. and then more 4,4-diethoxy-N-methylbutan-1-amine (0.32g, 1.84 mmol) was added. The reaction was heated to reflux and then more28% aqueous HCl (0.15 mL, 1.13 mmol) was added. The reaction was heatedto reflux for a further 3.5 h. The reaction was cooled and concentratedunder reduced pressure. The red brown residue was subjected to columnchromatography (silica gel, eluent: EtOAc followed by EtOAc:EtOH:NH₄OH90:10:1) to give the product (0.318 g, 46%).

(C)6-chloro-9-(2-cyclopentylethyl)-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole

37% aqueous formaldehyde (69 mg, 0.85 mmol) in acetonitrile (1 mL) wasadded to a refluxing solution of{2-[5-Chloro-1-(2-cyclopentyl-ethyl)-1H-indol-3-yl]-ethyl}-methyl-amine(283 mg, 0.77 mmol) in 5% trifluoroacetic acid in acetonitrile (5 mL)under a nitrogen atmosphere. The reaction was refluxed for 1.5 h. Thereaction was cooled and concentrated under reduced pressure. Theresulting dark red residue azeotroped with acetonitrile then dissolvedin ethyl acetate (50 mL) and washed with saturated aqueous sodiumhydrogen carbonate (20 mL). The organic layer was dried (Na₂SO₄),filtered and concentrated under reduced pressure to a dark residue (˜400mg). The residue was purified by column chromatography (silica gel,eluent: EtOAc followed by EtOAc:EtOH:NH₄OH 98:2:0.2) to give a brown oil(198 mg, 81%). The free base was converted to the hydrochloride bydissolving the solid in anhydrous diethyl ether (˜30 mL) under anitrogen atmosphere and filtering, 2M hydrochloride in diethyl ether(0.35 mL, 0.7 mmol) was added to the filtrate under a nitrogenatmosphere to form a precipitate. The solvent was removed under reducedpressure and the residue triturated with anhydrous diethyl ether whichwas removed under a reduced pressure and dried in vacuo over P₂O₅ togive the hydrochloride (183 mg) as an off-white solid.

Example 53b Preparation of Compound 35

37% aqueous formaldehyde (69 mg, 0.85 mmol) in acetonitrile (1 mL) wasadded to a refluxing solution of{2-[5-Chloro-1-(2-cyclopentyl-ethyl)-1H-indol-3-yl]-ethyl}-methyl-amine(283 mg, 0.77 mmol) in 5% trifluoroacetic acid in acetonitrile (5 mL)under a nitrogen atmosphere. The reaction mixture was refluxed for 1.5h, cooled and concentrated under reduced pressure. The resulting darkred residue was azeotroped with acetonitrile and dissolved in ethylacetate (50 mL) and washed with saturated aqueous sodium hydrogencarbonate (20 mL). The organic layer was dried (Na₂SO₄), filtered andconcentrated under reduced pressure to a dark residue (˜400 mg). Theresidue was purified by column chromatography (silica gel, eluent: EtOAcfollowed by EtOAc:EtOH:NH₄OH 98:2:0.2) to give a brown oil (198 mg,81%). The free base was converted to the hydrochloride by dissolving thesolid in anhydrous diethyl ether (approx. 30 mL) under a nitrogenatmosphere and filtered. 2M HCl solution in diethyl ether (0.35 mL, 0.7mmol) was added to the filtrate under a nitrogen atmosphere to form aprecipitate. The solvent was removed under reduced pressure and theresidue triturated with anhydrous diethyl ether which was removed undera reduced pressure and dried in vacuo over P₂O₅ to give thehydrochloride (183 mg) as an off-white solid. ¹H NMR (DMSO): 10.84 (bs,1H), 7.6 (s, 1H), 7.55 (d, 1H), 7.2 (d, 1H) 4.7 (bs, 1H), 4.4 (bs, 1H),4.1 (bs, 2H), 3.8-3.4 (m, 4H), 3.0 (s, 3H), 1.1-1.8 (m, 11H).

Example 54 Preparation of6-chloro-2,3,4,9-tetrahydro-2-methyl-9-(2-(3,3-dimethylcyclopentyl)ethyl)-1H-pyrido[3,4-b]indole(Compound 36, Scheme I)

The title compound is prepared by following General Methods 1, 3 and 4using 4-chlorophenylhydrazine hydrochloride,3-(2-bromoethyl)-1,1-dimethylcyclopentane, and triethylamine (GeneralMethod 1),1-(4-chlorophenyl)-1-(2-(3,3-dimethylcyclopentyl)ethyl)hydrazine and4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and2-(5-chloro-1-(2-(3,3-dimethylcyclopentyl)ethyl)-1H-indol-3-yl)-N-methylethanamine(Example 14), formaldehyde and TFA in acetonitrile (General Method 4).

Example 55 Preparation of6-chloro-2,3,4,9-tetrahydro-2-methyl-9-(2-(piperazin-1-yl)ethyl)-1H-pyrido[3,4-b]indole(Compound 37, Scheme I)

The title compound is prepared by following General Methods 1, 3 and 4using 4-chlorophenylhydrazine hydrochloride, tert-butyl4-(2-bromoethyl)piperazine-1-carboxylate, and triethylamine (GeneralMethod 1), N-Boc-1-(4-chlorophenyl)-1-(2-(piperazin-1-yl)ethyl)hydrazineand 4,4-diethoxy-N-methylbutan-1-amine (General Method 3), tert-butyl4-(2-(5-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)ethyl)piperazine-1-carboxylate,formaldehyde and TFA in acetonitrile (General Method 4), and Bocdeprotection by using TFA/dichloromethane.

Example 56a Preparation of2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-1-(4-methylpiperidin-1-yl)ethanone(Compound 38, Scheme IV)

The title compound is prepared by following General Methods 1, 3, and 4by using 4-chlorophenylhydrazine hydrochloride,1-(N-bromoacetyl)-4-methyl piperidine, and triethylamine (General Method1), 2-(1-(4-chlorophenyl)hydrazinyl)-1-(4-methylpiperidin-1-yl)ethanoneand 4,4-diethoxy-N-methylbutan-1-amine (General Method 3),2-(5-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)-1-(4-methylpiperidin-1-yl)ethanone,formaldehyde and TFA in acetonitrile (General Method 4).

(A)2-[N-(4-Chloro-phenyl)-hydrazinol-1-(4-methyl-piperidin-1-yl)-ethanone

Triethylamine (1.8 ml, 12.91 mmol) was added to a suspension of4-chlorophenyl hydrazine hydrochloride (0.8 g, 4.54 mmol) in ethanol (7mL). The reaction mixture was stirred for 10 min.1-(N-Bromoacetyl)-4-methyl piperidine (1 g, 4.54 mmol) was added and thereaction was heated to reflux for 5 h. The reaction mixture wasconcentrated under reduced pressure and the residue partitioned betweenchloroform and water. The organic layer was separated, dried (MgSO₄),filtered and concentrated to an orange oil. Purification of the productby column chromatography (silica gel, eluent: 2% methanol in chloroform)gave of the correct isomer (0.5 g, 39%).

(B)2-[5-Chloro-3-(2-methylamino-ethyl)-indol-1-yl]-1-(4-methyl-piperidin-1-yl)-ethanone

2-[N-(4-Chloro-phenyl)-hydrazino]-1-(methyl-piperidin-1-yl)-ethanone(0.75 g, 2.66 mmol) was dissolved in ethyl acetate (3 mL) and 4Mhydrochloride in dioxane (0.7 mL) was added. The mixture wasconcentrated under reduced pressure to a glassy oil/foam. This wasdissolved in a mixture of ethanol (4 mL) and water (2 mL) and heated to60° C. The 4,4-diethoxy-N-methylbutan-1-amine (0.47 g, 2.68 mmol) wasadded and then heated to 7080° C. 28% aqueous HCl (0.35 mL, 2.66 mmol)was added and the reaction heated at 80° C. for 1 h. More4,4-diethoxy-N-methylbutan-1-amine (0.2 g, 1.14 mmol) and 28% aqueousHCl (0.3 mL, 2.30 mmol) was added and heated for a further 3 h. Further4,4-diethoxy-N-methylbutan-1-amine (0.3 g, 1.71 mmol) was added andheated for a further 6 h. The reaction was concentrated under reducedpressure to give a dark brown oil. The oil was subjected to columnchromatography (silica gel, eluent: EtOAc:EtOH:NH₄OH 7:3:1) to give abrown oil (0.29 g). Further purification of the brown oil by columnchromatography (silica gel, eluent: EtOAc:EtOH:NH₄OH 7:3:1) gave pureproduct (179 mg, 19%).

(C)-2-(6-Chloro-2-methyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-1-(4-methyl-piperidin-1-yl)-ethanone

2-[5-Chloro-3-(2-methylamino-ethyl)-indol-1-yl]-1-(4-methyl-piperidin-1-yl)-ethanone(160 mg, 0.46 mmol) in 5% trifluoroacetic acid in acetonitrile (3 mL)was heated to reflux. 37% aqueous formaldehyde (0.06 mL) was added. Thereaction was refluxed for 10 min. The reaction was cooled andconcentrated under reduced pressure. The resulting oil was dissolved inethyl acetate and washed with saturated aqueous sodium hydrogencarbonate and brine. The organic layer was dried (MgSO₄), filtered andconcentrated under reduced pressure to give a yellow solid. The solidwas purified using the Waters Preparative LC-MS to give the product (50mg, 30%). The free base was converted to the hydrochloride by dissolvingthe product in methanol (4 mL) and 2M hydrochloride in diethyl ether wasadded. The solution was concentrated under reduced pressure to give abuff solid (50 mg). Further drying under high vacuum gave thehydrochloride salt (25 mg, 13.7%).

Example 56b Preparation of Compound 38

2-[5-Chloro-3-(2-methylamino-ethyl)-indol-1-yl]-1-(4-methyl-piperidin-1-yl)-ethanone(160 mg, 0.46 mmol) in 5% trifluoroacetic acid in acetonitrile (3 mL)was refluxed. 37% aqueous formaldehyde (0.06 mL) was added to thereaction and refluxed for additional 10 min, cooled and concentratedunder reduced pressure. The resulting oil was dissolved in ethyl acetateand washed with saturated aqueous sodium hydrogen carbonate and brine.The organic layer was dried (MgSO₄), filtered and concentrated underreduced pressure to give a yellow solid. The solid was purified usingthe Water s Preparative HPLC to yield the product (50 mg, 30%). The freebase was converted to the hydrochloride by dissolving the product inmethanol (4 mL) and 2M hydrochloride in diethyl ether was added. Thesolution was concentrated under reduced pressure to give a buff solid(50 mg). Further drying under high vacuum gave the hydrochloride salt(25 mg, 13.7%). ¹H NMR (CD₃OD): 7.6 (s, 1H), 7.39-7.46 (d, 1H), 7.2-7.3(d, 1H), 5.2-5.35 (q, 2H), 4.5-4.6 (d, 3H), 4.1-4.2 (d, 1H), 3.7-3.85(bs, 2H), 3.18-3.3 (m, 6H), 2.72-2.84 (t, 1H), 1.85-1.95 (q, 4H),1.1-1.4 (m, 1H), 1.1 (d, 3H).

Example 57 Preparation of2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-1-(4-methylpiperazin-1-yl)ethanone(Compound 39, Scheme IV)

The title compound is prepared by following General Methods 1, 3, 4, 5and 7 by using 4-chlorophenylhydrazine hydrochloride, ethylbromoacetate, and triethylamine (General Method 1), ethyl2-(1-(4-chlorophenyl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(5-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate, formaldehydeand TFA in acetonitrile (General Method 4), ethyl2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetateand NaOH (General Method 5), and2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)aceticacid, N-methylpiperazine and EDCI (General Method 7).

Example 58a Preparation of2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-1-(pyrrolidin-1-yl)ethanone(Compound 40, Scheme IV)

The title compound is prepared by following General Methods 1, 3, 4, 5and 7 by using 4-chlorophenylhydrazine hydrochloride, ethylbromoacetate, and triethylamine (General Method 1), ethyl2-(1-(4-chlorophenyl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(5-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate, formaldehydeand TFA in acetonitrile (General Method 4), ethyl2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetateand NaOH (General Method 5), and2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)aceticacid, pyrrolidine and EDCI (General Method 7).

Example 58b Preparation of Compound 40

2-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)aceticacid (0.1 g, 0.35 mmol) was dissolved in dichloromethane (4 mL) andcooled to 0° C., using an ice-bath; followed by drop-wise addition ofoxalyl chloride (0.054 g, 0.43 mmol) to the reaction mixture. Acatalytic amount (1 drop) of dimethyl formamide was added and thereaction mixture was stirred for 1 h at room temperature. Excess oxalylchloride was distilled away under reduced pressure. A solution ofpyrrolidine (0.031 g, 0.43 mmol) in dichloromethane (2 mL) and4-dimethylaminopyridine (0.044 g, 0.35 mmol) was added to this residue,under nitrogen at room temperature and stirred for 30 min. The reactionmixture was quenched with water and extracted with dichloromethane (2×10mL). The combined organic layer was washed with NaHCO₃ solution followedby HCl, dried over sodium sulfate and concentrated under reducedpressure to yield2-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-(pyrrolidin-1-yl)ethanoneas a TFA salt (10 mg) after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection volume 5mL). ¹H NMR (CD₃OD): 7.5 (s, 1H), 7.3 (d, 1H), 7.19 (d, 1H), 5.2-5.1 (m,1H), 5.0-4.9 (m, 1H), 4.4 (s, 2H), 4.3-4.2 (m, 2H), 4.0-3.9 (m, 2H), 3.5(s, 3H), 3.4 (t, 2H), 3.2-3.1 (bs, 2H), 2.05-1.9 (m, 4H).

Example 59 Preparation of2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-1-(3,3,4-trimethylpiperazin-1-yl)ethanone(Compound 41, Scheme IV)

The title compound is prepared by following General Methods 1, 3, 4, 5and 7 by using 4-chlorophenylhydrazine hydrochloride, ethylbromoacetate, and triethylamine (General Method 1), ethyl2-(1-(4-chlorophenyl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(5-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate, formaldehydeand TFA in acetonitrile (General Method 4), ethyl2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetateand NaOH (General Method 5), and2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)aceticacid, 1,2,2-trimethylpiperazine and EDCI (General Method 7).

Example 60 Preparation of2-(1,2,3,4-tetrahydro-2,5-dimethylpyrido[3,4-b]indol-9-yl)-1-(piperidin-1-yl)ethanone(Compound 42, Scheme IV)

The title compound is prepared by following General Methods 1, 3, 4, 5and 7 by using m-tolylhydrazine hydrochloride, ethyl bromoacetate, andtriethylamine (General Method 1), ethyl 2-(1-m-tolylhydrazinyl)acetateand 4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(4-methyl-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate, formaldehydeand TFA in acetonitrile (General Method 4), ethyl2-(1,2,3,4-tetrahydro-2,5-dimethylpyrido[3,4-b]indol-9-yl)acetate andNaOH (General Method 5), and2-(1,2,3,4-tetrahydro-2,5-dimethylpyrido[3,4-b]indol-9-yl)acetic acid,piperidine and EDCI (General Method 7).

Example 61a Preparation of3-(1,2,3,4-tetrahydro-2,6-dimethylpyrido[3,4-b]indol-9-yl)-1-(piperidin-1-yl)propan-1-one(Compound 43, Scheme IV)

The title compound is prepared by following General Methods 1, 3, 4, 5and 7 by using p-tolylhydrazine hydrochloride, ethyl 3-bromopropionate,and triethylamine (General Method 1), ethyl3-(1-p-tolylhydrazinyl)propanoate and 4,4-diethoxy-N-methylbutan-1-amine(General Method 3), ethyl3-(5-methyl-3-(2-(methylamino)ethyl)-1H-indol-1-yl)propanoate,formaldehyde and TFA in acetonitrile (General Method 4), ethyl3-(1,2,3,4-tetrahydro-2,6-dimethylpyrido[3,4-b]indol-9-yl)propanoate andNaOH (General Method 5), and3-(1,2,3,4-tetrahydro-2,6-dimethylpyrido[3,4-b]indol-9-yl)propanoicacid, piperidine and EDCI (General Method 7).

Example 61b Preparation of Compound 43

2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (100 mg, 0.5mmol), tetra n-butyl ammonium chloride (7 mg, 0.0025 mmol) and1-(piperidin-1-yl)prop-2-en-1-one (76 mg, 0.55 mmol) was dissolved in50% NaOH (3 mL) and the reaction mixture was heated overnight at 90° C.The reaction was monitored by TLC. After completion, the reactionmixture was extracted with ethyl acetate and water. The organic layerwas separated, dried over Na₂SO₄, and concentrated under reducedpressure to obtain3-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-(piperidin-1-yl)propan-1-oneas TFA salt (16 mg) after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection volume 5mL). ¹H NMR (CD₃OD): 1.25-1.3 (m, 4H), 1.41-1.6 (m, 2H), 2.4 (s, 3H),2.63-2.8 (m, 3H), 2.91-3.1 (m, 5H), 3.2-3.3 (m, 3H), 3.69-3.8 (m, 2H),4.25 (t, 2H), 4.42-4.5 (m, 1H), 4.8-4.9 (m, 1H), 7.0 (d, 1H), 7.25 (s,1H), 7.39 (d, 1H), 10.2 (bs, 1H).

Example 62a Preparation of4-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-1-(piperidin-1-yl)butan-1-one(Compound 44, Scheme IV)

The title compound is prepared by following General Methods 1, 3, 4, 5and 7 by using 4-chlorophenylhydrazine hydrochloride, ethyl4-bromobutyrate, and triethylamine (General Method 1), ethyl4-(1-(4-chlorophenyl)hydrazinyl)butanoate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl4-(5-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)butanoate,formaldehyde and TFA in acetonitrile (General Method 4), ethyl4-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)butanoateand NaOH (General Method 5), and4-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)butanoicacid, piperidine and EDCI (General Method 7).

Example 62b Preparation of Compound 44

Sodium hydride (0.027 g, 1.14 mmol) was dissolved inN,N-dimethylformamide.6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (0.1 g, 05mmol) in N,N-dimethylformamide was added at 0° C. to the NaH solutionand stirred for 0.5 h. 4-chloro-1-(piperidin-1-yl)butan-1-one (0.104 g,0.54 mmol) in N,N-dimethylformamide was added to the reaction mixturedrop-wise and stirred for 3 h. The reaction mixture was quenched withwater (2 mL) and N,N-dimethylformamide was evaporated under reducedpressure to yield4-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-(piperidin-1-yl)butan-1-oneas TFA salt (5 mg) after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection volume 5mL). ¹H NMR (CD₃OD): 7.49 (s, 1H), 7.42 (d, 1H), 7.2 (d, 1H), 4.4-4.6(m, 2H), 4.12-4.2 (m, 2H), 3.8-3.94 (m, 2H), 3.4-3.6 (m, 2H), 3.35-3.4(m, 2H), 3.10-3.2 (m, 5H), 2.35-2.42 (m, 2H), 1.95-2.1 (m, 2H), 1.6-1.7(m, 2H), 1.4-1.5 (m, 4H).

Example 63 Preparation of2-(7-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-1-(piperidin-1-yl)ethanone(Compound 45, Scheme IV)

The title compound is prepared by following General Methods 1, 3, 4, 5and 7 by using 3-chlorophenylhydrazine hydrochloride, ethylbromoacetate, and triethylamine (General Method 1), ethyl2-(1-(3-chlorophenyl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(6-chloro-3-(2-(methylamino)ethyl)-1H-indol-1-yl)acetate, formaldehydeand TFA in acetonitrile (General Method 4), ethyl2-(7-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetateand NaOH (General Method 5), and2-(7-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)aceticacid, piperidine and EDCI (General Method 7).

Example 64 Preparation of8-aza-2-(1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-1-(piperidin-1-yl)ethanone(Compound 46, Scheme IV)

The title compound is prepared by following General Methods 1, 3, 4, 5and 7 by using 1-(pyridin-2-yl)hydrazine hydrochloride and ethylbromoacetate (General Method 1), ethyl2-(1-(pyridin-2-yl)hydrazinyl)acetate and4,4-diethoxy-N-methylbutan-1-amine (General Method 3), ethyl2-(3-(2-(methylamino)ethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)acetate,formaldehyde and TFA in acetonitrile (General Method 4), ethyl8-aza-2-(1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetate andNaOH (General Method 5), and8-aza-2-(1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetic acid,piperidine and EDCI (General Method 7).

Example 65 Preparation of6-chloro-2,3,4,9-tetrahydro-2-methyl-9-(prop-2-ynyl)-1H-pyrido[3,4-b]indole(Compound 125, Scheme I)

The title compound was prepared by following General Methods 2, 3 and 4using 4-chlorophenylhydrazine hydrochloride, propargyl bromide, andtetra-n-butylammonium chloride (General Method 2),1-(4-chlorophenyl)-1-(prop-2-ynyl)hydrazine (Example 8) and4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and2-(5-chloro-1-(prop-2-ynyl)-1H-indol-3-yl)-N-methylethanamine (Example17), formaldehyde and TFA in acetonitrile (General Method 4).

(A) N-(4-Chloro-phenyl)-N-prop-2-ynyl-hydrazine

4-Chlorophenylhydrazine hydrochloride (550 mg, 3 mmol) was added to avigorously stirred mixture of tetra-n-butylammonium chloride (42 mg,0.15 mmol) in 50% aqueous sodium hydroxide (3 mL) followed by 80%propargyl bromide in toluene (490 mg, 3.3 mmol). The reaction wasstirred at room temperature for 20 h. The reaction was diluted withwater (30 mL) and extracted with chloroform (3×10 mL). The combinedorganic layer was dried (Na₂SO₄), filtered and concentrated underreduced pressure to a dark brown oil (530 mg). The oil was subjected tocolumn chromatography (silica gel, eluent: 50% dichloromethane inhexanes) to give an orange solid (260 mg, 48%).

(B) [2-(5-Chloro-1-prop-2-ynyl-1H-indol-3-yl)-ethyl]-methyl-amine

28% aqueous HCl (0.13 mL, 1 mmol) was added to a solution ofN-(4-Chloro-phenyl)-N-prop-2-ynyl-hydrazine (180 mg, 1 mmol) in ethanol(2 mL) under a nitrogen atmosphere. The reaction was heated to 60° C.(oil bath temperature) and 4,4-diethoxy-N-methylbutan-1-amine (175 mg, 1mmol) was added. The reaction was heated to 90° C. and 28% aqueous HCl(0.26 mL, 2 mmol) was added. The reaction heated at reflux for 6 h. Thereaction was cooled and stirred for 3 days. 28% aqueous HCl (0.26 mL, 2mmol) was added and then heated to reflux.4,4-diethoxy-N-methylbutan-1-amine (90 mg, 0.51 mmol) was added. Thereaction was reflux for a further 6 h. The reaction was cooled andconcentrated under reduced pressure. The residue was subjected to columnchromatography (silica gel, eluent: EtOAc followed by EtOAc:EtOH:NH₄OH90:10:1) to give a yellow orange oil (88 mg, 36%).

(C)6-chloro-2,3,4,9-tetrahydro-2-methyl-9-(prop-2-ynyl)-1H-pyrido[3,4-b]indole

37% aqueous formaldehyde (31 mg, 0.38 mmol) in acetonitrile (0.6 mL) wasadded to a refluxing solution of[2-(5-Chloro-1-prop-2-ynyl-1H-indol-3-yl)-ethyl]-methyl-amine (88 mg,0.30 mmol) in 5% trifluoroacetic acid in acetonitrile (3 mL) under anitrogen atmosphere. The reaction was refluxed for 1.5 h. The reactionwas cooled and concentrated under reduced pressure. The resulting oilwas dissolved in ethyl acetate (50 mL) and washed with saturated aqueoussodium hydrogen carbonate (10 mL). The organic layer was dried (Na₂SO₄),filtered and concentrated under reduced pressure to a dark buff solid(120 mg). The solid was purified by column chromatography (silica gel,eluent: EtOAc followed by EtOAc:EtOH:NH₄OH 90:10:1) to give a buff solid(63 mg, 68%). The free base was converted to the hydrochloride bydissolving the solid in anhydrous diethyl ether (˜20 mL) under anitrogen atmosphere and filtering, 2M hydrochloride in diethyl ether(0.15 mL, 0.3 mmol) was added to the filtrate under a nitrogenatmosphere to form a precipitate. The solvent was removed under reducedpressure and the residue triturated with anhydrous diethyl ether whichwas removed under a reduced pressure. The resulting buff solid was driedin vacuo over P₂O₅ to give the hydrochloride (66 mg, 93%).

Example 66 Preparation of Compound 92

2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-phenylethylmethanesulfonate (220 mg, 0.55 mmol) was dissolved inN-methyl-2-pyrrolidone (1.5 mL), KOH powder (216 mg, 3.8 mmol) was addedat RT and heated overnight at 100° C. The reaction was monitored byLCMS. Water was added to the reaction mixture, extracted with ethylacetate, dried over anhydrous sodium sulfate and evaporated underreduced pressure and purified by reverse phase chromatography to yieldTFA salt (33 mg). ¹H NMR (CDCl₃): 7.58-7.35 (m, 5H), 7.30-7.25 (m, 2H),7.13-7.10 (d, 1H), 6.65-6.61 (d, 1H), 3.85-3.75 (m, 2H), 3.65-3.6 (m,4H), 2.87 (s, 3H), 2.45 (s, 3H).

Example 67 Preparation of Compound 81

6-chloro-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (0.1 g,0.43 mmol) was dissolved in 50% NaOH (6 mL); 4-fluorophenethylmethanesulfonate (0.11 g, 0.51 mmol) and tetrabutylammonium bromide (7mg, 0.021 mmol) were added to the reaction mixture and heated overnightat 100° C. The reaction was monitored by LCMS, after completion, thereaction mixture was extracted with ethyl acetate and water, the organiclayer dried over sodium sulfate and concentrated under reduced pressure.The crude compound was purified by column chromatography to yield thedesired compound as a free base (0.060 g). ¹H NMR (CDCl₃): 7.47 (s, 1H),7.20 (d, 1H), 7.13 (d, 1H), 6.99-6.92 (m, 4H), 4.32-4.24 (m, 1H),4.12-4.03 (m, 1H), 3.43-3.38 (m, 1H), 3.28-3.0 (m, 2H), 3.0-3.90 (m,1H), 2.60-2.53 (m, 1H), 2.34 (s, 3H), 1.33 (d, 3H).

Example 68 Preparation of Compound 79

6-chloro-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200mg, 0.806 mmol) was dissolved in N-methyl-2-pyrrolidone (1.5 mL); KOHpowder (452 mg, 8.06 mmol) and 2-(4-fluorophenyl)-2-methyloxirane (147mg, 0.967 mmol) was added at RT and heated at 90° C. for 14 h. Thereaction was monitored by LCMS. Upon completion, the reaction mixturewas filtered and the product was purified by reverse phasechromatography to yield the title compound as the TFA salt (150 mg). ¹HNMR (CDCl₃): 7.37 (s, 1 h), 7.04-6.94 (m, 2H), 6.80-6.72 (m, 3H), 6.27(d, 1H), 4.28-4.13 (m, 2H), 3.81-3.70 (m, 1H), 3.64-3.56 (m, 2H), 3.08(s, 3H), 2.67-2.46 (m, 2H), 2.20-2.09 (m, 1H), 2.08-1.94 (m, 1H), 1.82(s, 3H), 1.27-1.20 (m, 3H).

Example 69 Preparation of Compound 55

6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (100 mg,0.45 mmol), was dissolved in N,N-dimethylformamide. CuI (9 mg, 0.045mmol), L-proline (11 mg, 0.091 mmol), and K₃PO₄ (194 mg, 0.91 mmol) wasadded to the reaction mixture and stirred for 10 min at roomtemperature, followed by drop-wise addition of tert-butyl4-(2-chloroacetyl)piperazine-1-carboxylate (143 mg, 0.54 mmol) andstirred at 90° C. for 12 h. After completion of the reaction, thereaction mixture was filtered through Celite, N,N-dimethylformamide wasevaporated under reduced pressure and extracted with ethyl acetate. Thecombined organic layer was dried over Na₂SO₄, and concentrated underreduced pressure. The crude compound was purified by Columnchromatography to give Boc-protected compound (0.150 mg). The compoundwas dissolved in HCl in ethanol (4 mL). The ethanol was evaporated toobtain2-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-(piperazin-1-yl)ethanoneas HCl salt (80 mg). ¹H NMR (CD₃OD): 7.52 (s, 1H), 7.24 (d, 1H), 7.15(dd, 1H), 5.19-5.23 (m, 2H), 4.71-4.79 (m, 2H), 4.25-4.30 (m, 2H),3.85-4.00 (m, 4H), 3.70-3.79 (m, 2H), 3.52 (s, 3H), 3.15-3.23 (m, 4H).

Example 70 Preparation of Compound 71

Sodium hydride (64 mg, 2.7 mmol) in N,N-dimethylformamide (10 mL) wascharged and stirred for 10 min at RT.6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (0.2 g, 0.9mmol) was added to the reaction mixture and stirred for 10 min, followedby addition of 2-phenyloxirane (163 mg, 1.3 mmol) and stirred at RTovernight. The reaction mixture was quenched with ice water, andextracted with ethyl acetate. The combined organic layer was dried overanhydrous sodium sulfate and evaporated under reduced pressure. Thecrude product was purified by reverse phase chromatography to yield TFAsalt (60 mg), which was converted to free base (15 mg). ¹H NMR (CDCl₃):7.50-7.40 (m, 1H), 7.38-7.22 (m, 5H), 7.20-7.05 (m, 2H), 4.98-4.90 (m,1H), 4.15-4.10 (m, 2H), 3.90-3.80 (d, 1H), 3.50-3.42 (d, 1H), 2.95-2.80(m, 4H), 2.55 (s, 3H).

Example 71 Preparation of Compound 70

Sodium hydride (64 mg, 2.7 mmol) in N,N-dimethylformamide (10 mL) wascharged and stirred for 10 min at RT.6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200 mg, 0.9mmol) was added to the reaction mixture and stirred for 10 min, followedby addition of 2-(3,4-dimethoxyphenyl)oxirane (245 mg, 1.3 mmol) andstirred at RT overnight. The reaction mixture was quenched with icewater and extracted with ethyl acetate. The combined organic layer wasdried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude product was purified by reverse phase chromatographyto yield TFA salt (70 mg), which was converted to free base (30 mg). ¹HNMR (CDCl₃): 7.47 (s, 1H), 7.22-7.10 (m, 2H), 6.85-6.80 (m, 2H),6.70-6.65 (d, 1H), 4.90-4.85 (t, 1H), 4.15-4.10 (d, 2H), 3.90 (s, 3H),3.78 (s, 3H), 3.75-3.70 (d, 1H), 3.50-3.40 (d, 1H), 2.95-2.70 (m, 4H),2.55 (s, 3H).

Example 72 Preparation of Compound 72

Sodium hydride (72 mg, 3.0 mmol) in N,N-dimethylformamide (10 mL) wascharged and stirred for 10 min at RT.2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200 mg, 1.0mmol) was added to the solution and stirred for 10 min, followed byaddition of 2-p-tolyloxirane (201 mg, 1.5 mmol) and stirred at RTovernight. The reaction mixture was quenched with ice water andextracted with ethyl acetate. The combined organic layer was dried overanhydrous sodium sulfate and evaporated under reduced pressure. Thecrude product was purified by reverse phase chromatography to yield TFAsalt (70 mg), which was converted to free base (40 mg). ¹H NMR (CDCl₃):7.40-7.18 (m, 6H), 7.05-7.00 9d, 1H), 5.00-4.95 (m, 1H), 4.10-4.05 (m,2H), 3.85-3.80 (d, 1H), 3.40-3.35 (d, 1H), 2.90-2.75 (m, 4H), 2.55 (s,3H), 2.50 (s, 3H), 2.35 (s, 3H).

Example 73 Preparation of Compound 125

37% aqueous formaldehyde (31 mg, 0.38 mmol) in acetonitrile (0.6 mL) wasadded to a refluxing solution of[2-(5-Chloro-1-prop-2-ynyl-1H-indol-3-yl)-ethyl]-methyl-amine (88 mg,0.30 mmol) in 5% trifluoroacetic acid in acetonitrile (3 mL) under anitrogen atmosphere and refluxed for an additional 1.5 h. The reactionwas cooled and concentrated under reduced pressure. The resulting oilwas dissolved in ethyl acetate (50 mL) and washed with saturated aqueoussodium hydrogen carbonate (10 mL). The organic layer was dried (Na₂SO₄),filtered and concentrated under reduced pressure to a dark buff solid(120 mg). The solid was purified by column chromatography (silica gel,eluent: EtOAc followed by EtOAc:EtOH:NH₄OH 90:10:1) to yield a buffsolid (63 mg, 68%). The free base was converted to the hydrochloride bydissolving the solid in anhydrous diethyl ether (˜20 mL) under anitrogen atmosphere and filtering. 2M hydrochloride in diethyl ether(0.15 mL, 0.3 mmol) was added to the filtrate under a nitrogenatmosphere to form a precipitate. The solvent was removed under reducedpressure and the residue triturated with anhydrous diethyl ether whichwas removed under a reduced pressure. The resulting buff solid was driedin vacuo over P₂O₅ to yield the hydrochloride (66 mg, 93%). ¹H NMR(DMSO): 11.4 (bs, 1H), 7.6 (d, 2H), 7.25 (d, 1H), 5.1 (s, 2H), 4.7 (bs,1H), 4.35 (bs, 1H), 3.7 (bs, 1H), 3.4 (bs, 3H), 3.0 (bs, 1H), 2.9 (s,3H).

Example 74 Preparation of Compound 90

1-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-2-(4-fluorophenyl)propan-2-ol (30 mg, 0.0806 mmol) was dissolved in 25% sulfuric acid, andthe reaction mixture was heated overnight at 60° C. The reaction wasmonitored by TLC. After completion of the reaction, pH of the reactionmixture was adjusted to 10-12 and extracted with ethyl acetate. Theorganic layer was dried over Na₂SO₄, and concentrated under reducedpressure. The crude compound was purified by preparative TLC. The purecompound was stirred in ethanolic HCl to yield HCl salt of(E)-6-chloro-9-(2-(4-fluorophenyl)prop-1-enyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(8 mg). ¹H NMR (CD₃OD):—7.63-7.70 (m, 2H), 7.60 (s, 1H), 7.10-7.20 (m,3H), 7.0 (s, 1H), 4.65 (d, 1H), 4.43 (d, 1H), 3.78-3.90 (m, 1H),3.52-3.60 (m, 2H), 3.10-3.25 (m, 5H), 1.96 (s, 3H).

Example 75 Preparation of Compound 57

Sodium hydride (0.120 g, 60%, 5.0 mmol) was washed with hexane forremoval of oil, dried under vacuum and dissolved inN,N-dimethylformamide.2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (0.5 g, 2.5 mmol)in N,N-dimethylformamide was added drop-wise to the reaction mixture at0° C. and stirred for 0.5 h. The solution of2-chloro-1-(piperidin-1-yl)ethanone (0.483 g, 3.0 mmol) inN,N-dimethylformamide was added drop-wise and the reaction mixture wasstirred at RT for 2 h. The reaction was monitored by TLC. Aftercompletion of the reaction, the reaction mixture quench with ice-water,the solid compound was filtered, the crude compound was washed withhexane and diethyl ether for removal of color impurities thenrecrystallized by using methanol to yield the desired compound (0.4 g).The crude product was stirred with ethanolic HCl to give HCl salt of2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-(piperidin-1-yl)ethanone.¹H NMR (DMSO): 11.22 (bs, 1H), 7.23-7.33 (m, 2H), 6.97 (d, 1H), 5.14 (d,1H), 5.0 (d, 1H), 4.57 (d, 1H), 4.13-4.22 (m, 1H), 3.61-3.69 (m, 1H),3.32-3.58 (m, 5H), 2.97-3.10 (m, 2H), 2.90 (s, 3H), 2.39 (s, 3H),1.51-1.67 (m, 4H), 1.35-1.48 (m, 2H).

Example 76 Preparation of Compound 64

Sodium hydride (54 mg, 2.2 mmol) was dissolved in N,N-dimethylformamide(7.5 mL) and stirred for 10 min.2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (150 mg, 0.75mmol) was added to the solution and stirred for 10 min, followed byaddition of 2-(oxiran-2-yl)pyridine (133 mg, 1.1 mmol) and stirredovernight at RT. The progress of the reaction was monitored by TLC andLCMS. The reaction mixture was quenched with ice water, extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate and evaporated under reduced pressure. Thecrude product was purified by reverse phase chromatography to get puretitle compound as TFA salt (27 mg). ¹H NMR (DMSO): 10.30-10.10 (m, 1H),8.70-8.55 (m, 1H), 7.95-7.50 (m, 2H), 7.45-7.05 (m, 2H), 7.00-6.75 (m,2H), 4.95-4.70 (m, 1H), 4.60-4.40 (m, 2H), 4.20-3.60 (m, 4H), 3.55-3.35(m, 2H), 3.00 (s, 3H), 2.38 (s, 3H).

Example 77 Preparation of Compound 65

Sodium hydride (48 mg, 2.0 mmol) was dissolved in N,N-dimethylformamide(7.5 mL) and stirred for 10 min.6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (150 mg,0.68 mmol) was added to the solution and stirred for 10 min, followed byaddition of 2-(oxiran-2-yl)pyridine (123 mg, 1.02 mmol) and stirredovernight at RT. The progress of the reaction was monitored by TLC andLCMS. The reaction mixture was quenched with ice water and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate and evaporated under reduced pressure. Thecrude product was purified by reverse phase chromatography to get puretitle compound as TFA salt (60 mg). ¹H NMR (DMSO): 10.50-10.2 (m, 1H),8.70-8.50 (m, 1H), 7.90-7.75 (m, 1H), 7.70-7.45 (m, 2H), 7.40-7.20 (m,2H), 7.15-6.95 (m, 2H), 4.95-4.75 (m, 1H), 4.65-4.50 (m, 2H), 4.40-4.20(m, 2H), 4.10-3.75 (m, 2H), 3.55-3.40 (m, 2H), 3.05 (s, 3H).

Example 78 Preparation of Compound 66

Sodium hydride (72 mg, 3.0 mmol) was dissolved in N,N-dimethylformamide(10 mL) and stirred for 10 min.2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200 mg, 1.0mmol) was added to the reaction mixture and stirred for 10 min, followedby addition of 2-(3,4-dimethoxyphenyl)oxirane (270 mg, 1.5 mmol) andstirred overnight at RT. The progress of the reaction was monitored byTLC and LCMS. The reaction mixture was quenched with ice water andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude product was purified by reverse phase chromatographyto get pure title compound as TFA salt (90 mg). ¹H NMR (DMSO):10.50-10.15 (m, 1H), 7.50-7.30 (m, 2H), 7.10-6.80 (m, 4H), 5.70-5.55 (m,1H), 4.90-4.65 (m, 2H), 4.30-4.05 (m, 3H), 3.85-3.75 (m, 8H), 3.50-3.25(m, 2H), 3.05 (s, 3H), 2.38 (s, 3H).

Example 79 Preparation of Compound 67

Sodium hydride (72 mg, 3.0 mmol) was dissolved in N,N-dimethylformamide(10 mL) and stirred for 10 min.2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200 mg, 1.0mmol) was added to the reaction mixture and stirred for 10 min, followedby addition of 2-phenyloxirane (180 mg, 1.5 mmol) and stirred overnightat RT. The progress of the reaction was monitored by TLC and LCMS. Thereaction mixture was quenched with ice water and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydroussodium sulfate and evaporated under reduced pressure. The crude productwas purified by reverse phase chromatography to get pure title compoundas TFA salt (3 mg). ¹H NMR (DMSO): 7.55-7.25 (m, 6H), 7.05-6.95 (m, 2H),5.70-5.65 (m, 1H), 4.85-4.80 (m, 2H), 4.30-4.10 (m, 3H), 3.75-3.65 (m,2H), 3.10-2.90 (m, 5H), 2.38 (s, 3H).

Example 80 Preparation of Compound 91

1-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-2-(4-fluorophenyl)propan-2-ol(70 mg, 0.198 mmol) was dissolved in 25% sulfuric acid and heatedovernight at 60° C. The progress of the reaction was monitored by TLC.After completion of the reaction, the pH was adjusted to 10-12 andextracted with ethyl acetate. The organic layer was dried over Na₂SO₄,and concentrated under reduced pressure. The crude compound was purifiedby preparative TLC. The pure compound was stirred in ethanolic HCl toyield HCl salt of(E)-9-(2-(4-fluorophenyl)prop-1-enyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(10 mg). ¹H NMR (CD₃OD): 7.60-7.70 (m, 2H), 7.36 (s, 1H), 7.06-7.22 (m,3H), 6.96 (s, 1H), 4.65 (d, 1H), 4.40 (d, 1H), 3.84-3.96 (m, 1H),3.50-3.60 (m, 2H), 3.06-3.20 (m, 5H), 2.43 (s, 3H), 2.0 (s, 3H).

Example 81 Preparation of Compound 54

2-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)aceticacid (100 mg, 0.35 mmol) was dissolved in dichloromethane (4 mL) andcooled to 0° C. Oxalyl chloride (0.055 g, 0.43 mmol) was added drop-wiseunder dry conditions, a catalytic amount of N,N-dimethylformamide wasadded and the reaction mixture was stirred at RT for 1 h. Oxalylchloride was evaporated under reduced pressure to obtain thecorresponding acid chloride. The acid chloride was quenched withmethanol; the excess methanol was evaporated under reduced pressure; andthe residue was purified by reversed phase chromatography to yieldmethyl2-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)acetateas TFA salt (3.0 mg). ¹H NMR (CD₃OD): 7.5 (s, 1H), 7.4 (d, 1H), 7.2 (d,1H), 5.0-4.9 (m, 2H), 4.5 (s, 2H), 4.1 (m, 1H), 3.90 (m, 1H), 3.8 (s,3H), 3.5 (s, 3H), 3.2 (m, 2H).

Example 82 Preparation of Compound 56

6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (100 mg,0.45 mmol), was dissolved in N,N-dimethylformamide. CuI (9 mg, 0.045mmol), L-proline (11 mg, 0.091 mmol) and K₃PO₄ (194 mg, 0.91 mmol) wasadded to the reaction mixture and stirred for 10 min. at roomtemperature. 5-(3-bromopropyl)-2-methylpyridine (116 mg, 0.54 mmol) wasadded drop-wise and the reaction mixture was heated at 90° C. for 12 h.After completion of the reaction, the reaction mixture was filteredthrough Celite. N,N-dimethylformamide was evaporated under reducedpressure and extracted with ethyl acetate. The organic layer was driedover Na₂SO₄, and concentrated under reduced pressure to obtain6-chloro-2-methyl-9-(3-(6-methylpyridin-3-yl)propyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoleas TFA salt (35 mg) after purification by reverse-phase chromatography(C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA inacetonitrile, Gradient: 10% B to 80% B in 30 min, injection volume 5mL). ¹H NMR (DMSO): 11.40 (bs, 1H), 8.62 (s, 1H), 8.1 7 (d, 1H), 7.69(d, 1H), 7.58 (s, 1H), 7.45 (d, 1H), 7.17 (d, 1H), 4.64-4.79 (m, 2H),3.43-3.48 (t, 4H), 3.18 (s, 3H), 3.03-3.10 (m, 2H), 2.71-2.79 (m, 2H),2.60 (s, 3H), 2.10-2.25 (m, 2H).

Example 83 Preparation of Compound 59

Sodium hydride (31 mg, 1.3 mmol) was dissolved in THF.6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (100 mg,0.045 mmol) in THF was added drop-wise at 0° C. to the NaH solution andstirred for 0.5 h. The solution of 2-(2-fluorophenyl)oxirane (94 mg,0.08 mmol) in THF was added drop-wise to the reaction mixture andstirred at RT for 2 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was quenchedwith ice-water, THF was evaporated and the aqueous layer was extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate. The crude compound was purified by column chromatography toyield desired compound (20 mg). The product was stirred in ethanolic HClto yield2-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-(2-fluorophenyl)ethanolhydrochloride salt. ¹H NMR (CD₃OD): 7.44-7.60 (m, 2H), 7.20-7.28 (dd,2H), 7.14-7.22 (m, 3H), 5.30 (dd, 2H), 4.39-4.60 (m, 2H), 4.1-4.3 (m,2H), 3.8-3.83 (m, 1H), 3.42-3.54 (m, 2H), 3.18 (s, 3H).

Example 84 Preparation of Compound 60

Sodium hydride (36 mg, 1.5 mmol) was dissolved in THF.2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]in dole (100 mg, 0.05mmol) in THF was added drop-wise at 0° C. to the NaH solution and thereaction mixture stirred for 0.5 h. The solution of2-(2-fluorophenyl)oxirane (103 mg, 0.075 mmol) in THF was addeddrop-wise to the react ion mixture and stirred at RT for 2 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with ice-water, THF wasevaporated and aqueous layer was extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate. The crudecompound was purified by column chromatography to yield desired compound(30 mg) which was stirred in ethanolic HCl to yield2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-(2-fluorophenyl)ethanolhydrochloride salt. ¹H NMR (CD₃OD): 7.55 (m, 1H), 7.30 (m, 2H), 7.25 (d,1H), 7.12 (m, 2H), 7.05 (d, 1H), 5.30 (m, 1H), 4.40 (d, 2H), 4.10 (m,2H), 3.10 (s, 3H), 3.0 (m, 2H), 2.80 (m, 2H), 2.40 (s, 3H).

Example 85 Preparation of Compound 61

Sodium hydride (120 mg, 60%, 3.0 mmol) was washed with hexane forremoval of oil, dried under vacuum and dissolved inN,N-dimethylformamide.2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200 mg, 1.0mmol) in N,N-dimethylformamide was added drop-wise at 0° C. to the NaHsolution and stirred for 0.5 h. The solution of2-(4-fluorophenyl)-2-methyloxirane (182 mg, 1.2 mmol) inN,N-dimethylformamide was added drop-wise to the reaction mixture andstirred at RT for 2 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was quenchedwith ice-water, N,N-dimethylformamide was evaporated and aqueous layerwas extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate. The crude compound was purified by preparativeTLC, to yield the desired compound (72 mg), which was stirred inethanolic HCl to yield1-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-2-(4-fluorophenyl)propan-2-olhydrochloride salt. ¹H NMR (CD₃OD): 7.44-7.57 (m, 1H), 7.55-7.43 (m,1H), 7.20-7.26 (m, 1H), 7.11-7.19 (m, 1H), 6.83-7.03 (m, 3H), 4.22-4.38(m, 2H), 4.10-4.18 (m, 1H), 3.99-4.06 (m, 1H), 3.70-3.81 (m, 2H),3.40-3.50 (m, 2H), 3.10 (s, 3H), 2.30-2.34 (m, 3H), 1.62 (d, 1.5H), 1.51(d, 1.5H).

Example 86 Preparation of Compound 62

Sodium hydride (62 mg, 2.58 mmol) was dissolved inN,N-dimethylformamide.6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200 mg,0.90 mmol) in N,N-dimethylformamide was added drop-wise at 0° C. to theNaH solution and stirred for 0.5 h. The solution of2-(4-fluorophenyl)-2-methyloxirane (165 mg, 2.7 mmol) inN,N-dimethylformamide was added drop-wise to the reaction mixture andstirred at RT for 2 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was quenchedwith ice-water, N,N-dimethylformamide was evaporated and the aqueouslayer was extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate. The crude compound was purified by preparativeTLC, to yield the desired compound as free base (35 mg) which wasstirred in ethanolic HCl to yield1-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-2-(4-fluorophenyl)propan-2-ol hydrochloride salt. ¹H NMR (CD₃OD): 7.36-7.52 (m, 3H),7.14-7.22 (m, 1H), 6.84-7.07 (m, 3H), 4.42-4.52 (d, 1H), 4.20-4.37 (m,3H), 4.04-4.10 (d, 1H), 3.76-3.84 (m, 1H), 3.40-3.58 (m, 2H), 3.10 (s,3H), 1.62 (s, 1.5H), 1.57 (s, 1.5H).

Example 87 Preparation of Compound 58

Sodium hydride (26 mg, 1.1 mmol) was dissolved in THF.6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (100 mg,0.45 mmol) in THF was added drop-wise at 0° C. to the NaH solution andstirred for 0.5 h. The solution of 2-chloro-1-(piperidin-1-yl)ethanone(88 mg, 0.54 mmol) in THF was added drop-wise to the reaction mixtureand stirred at RT for 2 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was quenchedwith ice-water, THF was evaporated and the aqueous layer was extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate. The crude compound was purified by column chromatography toyield desired compound as free base (75 mg). The free base was stirredwith ethanolic HCl to give HCl salt of2-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-(piperidin-1-yl)ethanone. ¹H NMR(DMSO): 10.98 (bs, 1H), 7.58 (s, 1H), 7.44 (d, 1H), 7.15 (d, 1H),5.05-5.23 (m, 2H), 4.51-4.63 (m, 1H), 4.18-4.27 (m, 1H), 3.63-3.73 (m,2H), 3.50-3.60 (m, 4H), 3.00-3.07 (m, 2H), 2.97 (s, 3H), 1.60-1.69 (m,4H), 1.40-1.45 (m, 2H).

Example 88 Preparation of Compound 83

Sodium hydride (0.040 g, 60%, 1.0 mmol) was washed with hexane forremoval of oil, dried under vacuum and dissolved in THF.6-chloro-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (0.1g, 0.40 mmol) in THF was added drop-wise at 0° C. to the NaH solutionand stirred for 0.5 h. The solution of2-chloro-1-(piperidin-1-yl)ethanone (0.078 g, 0.48 mmol) in THF wasadded drop-wise to the reaction mixture and stirred at RT for 2 h. Theprogress of the reaction was monitored by TLC. After completion of thereaction, the reaction mixture was quenched with ice-water, extractedwith ethyl acetate and brine, and the crude compound was purified bycolumn chromatography to yield the desired compound as a free base (50mg). ¹H NMR (CDCl₃): 7.42 (s, 1H), 7.10-7.01 (m, 2H), 4.81 (d, 1H), 4.61(d, 1H), 3.61-3.38 (m, 4H), 3.28-3.18 (m, 1H), 2.99-2.83 (m, 2H), 2.48(s, 3H), 1.80-1.48 (m, 10H), 1.08 (t, 3H).

Example 89 Preparation of Compound 82

Sodium hydride (0.043 g, 60%, 1.0 mmol) was washed with hexane forremoval of oil, dried under vacuum and dissolved in THF.6-chloro-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (0.1 g,0.43 mmol) in THF was added drop-wise at 0° C. to the NaH solution andstirred for 0.5 h. The solution of 2-chloro-1-(piperidin-1-yl)ethanone(0.083 g, 0.51 mmol) in THF was added drop-wise to the reaction mixtureand stirred at RT for 2 h. The progress of the reaction was monitored byTLC. After completion of the reaction, the reaction mixture was quenchedwith ice-water, extracted with ethyl acetate and brine, and the crudecompound was purified by column chromatography to yield the desiredcompound as a free base (40 mg). ¹H NMR (CDCl₃): 7.42 (s, 1H), 7.18 (d,1H), 7.06 (d, 1H), 4.82 (d, 1H), 4.62 (d, 1H), 3.9-3.82 (m, 1H), 3.6-3.4(m, 2H), 3.3-3.2 (m, 1H), 3.0-2.8 (m, 2H), 2.7-2.6 (m, 1H), 2.58 (s,3H), 1.75-1.50 (m, 4H), 1.4 (d, 3H), 1.3-1.2 (m, 4H).

Example 90 Preparation of Compound 77

Tetrabutylammonium bromide (13 mg, 0.04 mmol) was dissolved in 50%aqueous sodium hydroxide (6 ml), and stirred for 10 min at RT.6-chloro-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200mg, 0.8 mmol) was added and stirred for 10 min at RT followed byaddition of 2-(6-methylpyridin-3-yl)ethyl methanesulfonate (200 mg, 0.97mmol). The reaction mixture was stirred overnight at 90° C. The progressof the reaction was monitored by TLC and LCMS. The reaction mixture wascooled to RT, extracted with ethyl acetate, the organic layer was driedover anhydrous sodium sulfate and concentrated. The crude product waspurified by column chromatography to yield the title compound as freebase (30 mg). ¹H NMR (CDCl₃): 8.20-7.80 (m, 2H), 7.50 (s, 1H), 7.23 (s,1H), 7.20-7.00 (m, 2H), 4.45-4.38 (m, 1H), 4.10-4.00 (m, 1H), 3.30-2.80(m, 8H), 2.50 (s, 3H), 2.23 (s, 3H), 1.39-1.25 (m, 1H), 1.20-1.00 (m,3H).

Example 91 Preparation of Compound 78

Tetrabutylammonium bromide (6 mg, 0.02 mmol) was dissolved in 50%aqueous sodium hydroxide (5 ml), stirred for 10 min at RT.6-chloro-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (100mg, 0.4 mmol) was added and stirred for 10 min at RT, followed byaddition of 4-fluorophenethyl methanesulfonate (105 mg, 0.48 mmol). Thereaction mixture was stirred overnight at 100° C. The progress of thereaction was monitored by TLC and LCMS. The reaction mixture was cooledto RT, extracted with ethyl acetate, the organic layer was dried overanhydrous sodium sulfate and concentrated. The crude product waspurified by column chromatography to yield the title compound as freebase (57 mg). ¹H NMR (CDCl₃): 7.50 (s, 1H), 7.22 (d, 1H), 7.18 (d, 1H),7.00-6.90 (m, 4H), 4.40-4.30 (m, 1H), 4.19-4.00 (m, 1H), 3.20-3.02 (m,2H), 3.00-2.90 (m, 2H), 2.87-2.80 (m, 2H), 2.50-2.41 (m, 1H), 2.22 (s,3H), 1.70-1.60 (m, 2H), 1.05 (t, 3H).

Example 92 Preparation of Compound 80

Tetrabutylammonium bromide (6 mg, 0.02 mmol) was dissolved in 50%aqueous sodium hydroxide (6 ml) and stirred for 10 min at RT.6-chloro-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (100 mg,0.4 mmol) was added and stirred for 10 min at RT, followed by additionof 2-(6-methylpyridin-3-yl)ethyl methanesulfonate (110 mg, 0.51 mmol).The reaction mixture was stirred overnight at 100° C. The progress ofthe reaction was monitored by TLC and LCMS. The reaction mixture wascooled to RT, extracted with ethyl acetate, the organic layer was driedover anhydrous sodium sulfate and concentrated. The crude product waspurified by column chromatography to yield the title compound as freebase (40 mg). ¹H NMR (CDCl₃): 8.14 (s, 1H), 7.15 (s, 1H), 7.20 (d, 1H),7.15-7.06 (m, 2H), 7.00 (d, 1H), 4.36-4.28 (m, 1H), 4.08-4.00 (m, 1H),3.40-3.38 (q, 1H), 3.38-3.22 (m, 2H), 3.17-3.00 (m, 2H0, 2.97-2.77 (m,2H), 2.48 (s, 3H), 2.24 (s, 3H), 1.36 (d, 3H).

Example 93 Preparation of Compound 86

Tetrabutylammonium bromide (6.5 mg, 0.02 mmol) was dissolved in 50%aqueous sodium hydroxide (5 ml) and stirred for 10 min at RT.6-chloro-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (100mg, 0.403 mmol) was added and stirred for 10 min at RT, followed byaddition of 2-(trifluoromethyl)-5-vinylpyridine (84 mg, 0.48 mmol). Thereaction mixture was stirred overnight at 110° C. The progress of thereaction was monitored by TLC and LCMS. The reaction mixture was cooledto RT, extracted with ethyl acetate; the organic layer was dried overanhydrous sodium sulfate and concentrated. The crude product waspurified by column chromatography to yield the title compound (50 mg).¹H NMR (CDCl₃): 8.28 (s, 1HO, 7.52-7.42 (m, 2H), 7.28-7.10 (m, 3H),4.48-4.38 (m, 1H), 4.15-4.00 (m, 1H), 3.30-3.20 (m, 1H), 3.17-3.00 (m,2H), 2.86-2.56 (m, 3H), 2.47-2.40 (m, 1H), 2.10 (s, 3H), 1.70-1.50 (m,2H), 1.02 (t, 3H).

Example 94 Preparation of Compound 52

Ethyl2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetate(0.3 g, 2.9 mmol) in THF (10 mL) was added to a solution of sodiumhydroxide (0.177 g, 2.9 mmol) in water (3 mL) and heated at 75° C. for 1h. The progress of the reaction was monitored by TLC. After completionof the reaction, the solvent was removed; water (10 mL) was added to theresidue and the aqueous layer was washed with ethyl acetate (2×10 mL).The pH of aqueous layer was adjusted to 2-3, and the aqueous layer waswashed with ethyl acetate. The aqueous layer was evaporated, the residuewas extracted with methanol, filtered, the filtrate was concentratedunder reduced pressure to yield2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)aceticacid (175 mg). ¹H NMR (CD₃OD): 7.50 (s, 1H) 7.30 (d, 1H), 7.10 (d, 1H),5.1 (d, 1H), 5.0 (d, 1H), 4.4 (s, 2H), 4.2 (m, 1H), 4.0 (m, 1H), 3.4 (s,3H), 3.2 (m, 2H).

Example 95 Preparation of Compound 53

Ethyl 2-(1,2,3,4-tetrahydro-2,6-dimethylpyrido[3,4-b]indol-9-yl)acetate(0.35 g, 1.2 mmol) in THF (10 mL) was added to a solution of sodiumhydroxide (0.146 g, 3.6 mmol) in water (3 mL) and heated at 75° C. for 1h. The progress of the reaction was monitored by TLC. After completionof the reaction, the solvent was removed; water (10 mL) was added to theresidue and the aqueous layer was washed with ethyl acetate (2×10 mL).The pH of aqueous layer was adjusted to 2-3, and the aqueous layer waswashed with ethyl acetate. The aqueous layer was evaporated, the residuewas extracted with methanol, filtered, the filtrate was concentratedunder reduced pressure to yield2-(1,2,3,4-tetrahydro-2,6-dimethylpyrido[3,4-b]indol-9-yl)acetic acid(65 mg). ¹H NMR (CD₃OD): 7.30 (s, 1H) 7.20 (d, 1H), 7.0 (d, 1H), 5.1 (d,1H), 4.8 (d, 1H), 4.18 (m, 1H), 4.0 (s, 2H), 3.81 (m, 1H), 3.42 (s, 3H),3.15 (bs, 2H), 2.4 (s, 3H).

Example 96 Preparation of Compound 114

6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (69 mg, 0.31mmol) was dissolved in DMF (6 mL). To this solution was added CuI (6 mg,0.031 mmol), L-proline (7 mg, 0.063 mmol), K₃PO₄ (134 mg, 0.63 mmol).The reaction mixture was stirred for 10 min at room temperature followedby addition of 4-(1-bromoprop-1-en-2-yl)-1,2-dichlorobenzene (100 mg,0.378 mmol). The reaction mixture was heated at 80° C. overnight.Solvent was evaporated under reduced pressure; the residue was dilutedwith brine and extracted with ethyl acetate. Organic layer was driedover Na₂SO₄, and concentrated under reduced pressure. The crude productwas purified by silica gel chromatography to obtain 28 mg of6-chloro-9-(2-(3,4-dichlorophenyl)prop-1-enyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (DMSO) OXALATE SALT 7.95 (s, 1H), 7.62 (m, 3H), 7.30 (d, 1H),7.20 (m, 2H), 4.30 (m, 2H), 3.40 (m, 2H), 3.0 (m, 2H), 2.82 (s, 3H),1.90 (s, 3H).

Example 97 Preparation of Compound 112

6-chloro-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (89mg, 0.36 mmol) was dissolved in DMF (6 mL). To this solution was addedCuI (8 mg, 0.035 mmol), L-proline (9 mg, 0.086 mmol), K₃PO₄ (183 mg,0.862 mmol). The reaction mixture was stirred for 10 min at roomtemperature followed by addition of4-(1-bromoprop-1-en-2-yl)-1,2-difluorobenzene (100 mg, 0.431 mmol). Thereaction mixture was heated at 80° C. overnight. Solvent was evaporatedunder reduced pressure; the residue was diluted with brine and extractedwith ethyl acetate. Organic layer was dried over Na₂SO₄, andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography to obtain 19 mg of6-chloro-9-(2-(3,4-difluorophenyl)prop-1-enyl)-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (CD₃OD) OXALATE SALT 7.60 (t, 2H), 7.42 (m, 1H), 7.38 (m, 1H),7.22 (m, 2H), 7.10 (s, 1H), 4.60 (m, 1H), 3.80 (m, 2H), 3.60 (m, 1H),3.20 (m, 1H), 3.05 (s, 3H), 2.10 (m, 2H), 1.90 (s, 3H), 1.10 (t, 3H).

Example 98 Preparation of Compound 111

6-chloro-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (84 mg,0.36 mmol) was dissolved in DMF (6 mL). To this solution was added CuI(8 mg, 0.035 mmol), L-proline (9 mg, 0.086 mmol), K₃PO₄ (183 mg, 0.862mmol). The reaction mixture was stirred for 10 min at room temperaturefollowed by addition of 4-(1-bromoprop-1-en-2-yl)-1,2-difluorobenzene(100 mg, 0.431 mmol). The reaction mixture was heated at 80° C.overnight. Solvent was evaporated under reduced pressure, the residuewas diluted with brine and extracted with ethyl acetate. Organic layerwas dried over Na₂SO₄, and concentrated under reduced pressure. Thecrude product was purified by silica gel chromatography to obtain 43 mgof6-chloro-9-(2-(3,4-difluorophenyl)prop-1-enyl)-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (CD₃OD) OXALATE SALT 7.62 (m, 1H), 7.60 (s, 1H), 7.50 (m, 1H),7.36 (m, 1H), 7.22 (m, 2H), 7.05 (s, 1H), 4.80 (m, 2H), 3.60 (m, 1H),3.10 (m, 2H), 3.0 (s, 3H), 1.90 (s, 3H), 1.60 (d, 3H).

Example 99 Preparation of Compound 121

2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (68 mg, 0.34mmol) was dissolved in DMF (5 mL). To this solution was added CuI (6 mg,0.034 mmol), L-proline (8 mg, 0.068 mmol), K₃PO₄ (145 mg, 0.68 mmol).The reaction mixture was stirred for 10 min at room temperature followedby addition of 4-(1-bromoprop-1-en-2-yl)-2-fluoro-1-methoxybenzene (100mg, 0.408 mmol). The reaction mixture was heated at 80° C. overnight.Solvent was evaporated under reduced pressure, the residue was dilutedwith brine and extracted with ethyl acetate. Organic layer was driedover Na₂SO₄, and concentrated under reduced pressure. The crude productwas purified by silica gel chromatography to obtain 35 mg of9-(2-(3-fluoro-4-methoxyphenyl)prop-1-enyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (DMSO) OXALATE SALT 7.58 (d, 1H), 7.42 (d, 1H), 7.30 (s, 1H),7.20 (t, 1H), 7.10 (m, 2H), 6.98 (d, 1H), 4.20 (m, 2H), 3.90 (s, 3H),3.60 (m, 2H), 2.95 (m, 2H), 2.80 (s, 3H), 2.40 (s, 3H), 1.85 (s, 3H).

Example 100 Preparation of Compound 122

6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (75 mg, 0.34mmol) was dissolved in DMF (5 mL). To this solution was added CuI (6 mg,0.034 mmol), L-proline (8 mg, 0.068 mmol), K₃PO₄ (145 mg, 0.68 mmol).The reaction mixture was stirred for 10 min at room temperature followedby addition of 4-(1-bromoprop-1-en-2-yl)-2-fluoro-1-methoxybenzene (100mg, 0.408 mmol). The reaction mixture was heated at 80° C. overnight.Solvent was evaporated under reduced pressure, the residue was dilutedwith brine and extracted with ethyl acetate. Organic layer was driedover Na₂SO₄, and concentrated under reduced pressure. The crude productwas purified by silica gel chromatography to obtain 40 mg of6-chloro-9-(2-(3-fluoro-4-methoxyphenyl)prop-1-enyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (DMSO) OXALATE SALT 7.60 (m, 2H), 7.42 (d, 1H), 7.25 (d, 2H),7.18 (t, 1H), 7.10 (s, 1H), 4.10 (m, 2H), 3.90 (s, 3H), 3.50 (m, 2H),2.95 (m, 2H), 2.78 (s, 3H), 1.82 (s, 3H).

Example 101 Preparation of Compound 129

6-chloro-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (248mg, 1.00 mmol) was dissolved in toluene (4 mL) and K₂CO₃ (276 mg, 0.2mmol), CuSO₄.5H₂O (249 mg, 0.01 mmol) and 1,10-phenanthroline (36 mg,0.2 mmol) were added. The reaction mixture was stirred for 10 min and asolution of 1-(bromoethynyl)-4-fluorobenzene (220 mg, 1.1 mmol) toluene(2 mL) was added. The reaction mixture was purged with nitrogen andheated at 80-85° C. overnight. Solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography (100-200 mesh) using 0-25% ethyl acetate-hexane aseluent. ¹H NMR (DMSO) OXALATE SALT 7.62 (m, 4H), 7.30 (m, 3H), 4.10 (m,2H), 3.12 (m, 2H), 2.85 (m, 1H), 2.60 (s, 3H), 2.0 (m, 2H), 1.10 (t,3H).

Example 102 Preparation of Compound 109

2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (72 mg, 0.359mmol) was dissolved in DMF (5 mL). To this solution was added CuI (8 mg,0.035 mmol), L-proline (9 mg, 0.086 mmol), K₃PO₄ (183 mg, 0.862 mmol).The reaction mixture was stirred for 10 min at room temperature followedby addition of 4-(1-bromoprop-1-en-2-yl)-1,2-difluorobenzene (100 mg,0.431 mmol). The reaction mixture was heated at 80° C. overnight.Solvent was evaporated under reduced pressure; the residue was dilutedwith brine and extracted with ethyl acetate. Organic layer was driedover Na₂SO₄, and concentrated under reduced pressure. The crude productwas purified by silica gel chromatography to obtain 74 mg of9-(2-(3,4-difluorophenyl)prop-1-enyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (DMSO) OXALATE SALT 7.80 (m, 1H), 7.50 (m, 2H), 7.30 (s, 1H),7.20 (s, 1H), 7.15 (d, 1H), 7.0 (d, 1H), 4.22 (m, 2H), 3.40 (m, 2H),2.90 (m, 2H), 2.82 (s, 3H), 2.40 (s, 3H), 1.90 (s, 3H).

Example 103 Preparation of Compound 110

6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (79 mg, 0.35mmol) was dissolved in DMF (6 mL). To this solution was added CuI (8 mg,0.035 mmol), L-proline (9 mg, 0.086 mmol), K₃PO₄ (183 mg, 0.862 mmol).The reaction mixture was stirred for 10 min at room temperature followedby addition of 4-(1-bromoprop-1-en-2-yl)-1,2-difluorobenzene (100 mg,0.431 mmol). The reaction mixture was heated at 80° C. overnight.Solvent was evaporated under reduced pressure, the residue was dilutedwith brine and extracted with ethyl acetate. Organic layer was driedover Na₂SO₄, and concentrated under reduced pressure. The crude productwas purified by silica gel chromatography to obtain 60 mg of6-chloro-9-(2-(3,4-difluorophenyl)prop-1-enyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (DMSO) OXALATE SALT 7.80 (m, 1H), 7.60 (s, 1H), 7.50 (m, 2H),7.25 (d, 1H), 7.15 (s, 2H), 4.10 (m, 2H), 3.30 (m, 2H), 2.95 (m, 2H),2.78 (s, 3H), 1.82 (s, 3H).

Example 104 Preparation of Compound 116

6-chloro-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (78mg, 0.31 mmol) was dissolved in DMF (5 mL). To this solution was addedCuI (6 mg, 0.031 mmol), L-proline (7 mg, 0.063 mmol), K₃PO₄ (134 mg,0.63 mmol). The reaction mixture was stirred for 10 min at roomtemperature followed by addition of4-(1-bromoprop-1-en-2-yl)-1,2-dichlorobenzene (100 mg, 0.378 mmol). Thereaction mixture was heated at 80° C. overnight. Solvent was evaporatedunder reduced pressure, the residue was diluted with brine and extractedwith ethyl acetate. Organic layer was dried over Na₂SO₄, andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography to obtain 36 mg of6-chloro-9-(2-(3,4-dichlorophenyl)prop-1-enyl)-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (DMSO) OXALATE SALT 7.95 (s, 1H), 7.76 (d, 1H), 7.65 (m, 2H),7.30 (s, 1H), 7.20 (m, 2H), 3.40 (m, 3H), 2.90 (m, 4H), 2.70 (s, 3H),1.90 (s, 3H), 0.9 (t, 3H).

Example 105 Preparation of Compound 115

6-chloro-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (74 mg,0.31 mmol) was dissolved in DMF (5 mL). To this solution was added CuI(6 mg, 0.031 mmol), L-proline (7 mg, 0.063 mmol), K₃PO₄ (134 mg, 0.63mmol). The reaction mixture was stirred for 10 min at room temperaturefollowed by addition of 4-(1-bromoprop-1-en-2-yl)-1,2-dichlorobenzene(100 mg, 0.378 mmol). The reaction mixture was heated at 80° C.overnight. Solvent was evaporated under reduced pressure, the residuewas diluted with brine and extracted with ethyl acetate. Organic layerwas dried over Na₂SO₄, and concentrated under reduced pressure. Thecrude product was purified by silica gel chromatography to obtain 48 mgof6-chloro-9-(2-(3,4-dichlorophenyl)prop-1-enyl)-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (DMSO) OXALATE SALT 8.0 (d, 1H), 7.76 (d, 1H), 7.65 (m, 2H), 7.25(m, 2H), 7.18 (d, 1H), 4.50 (m, 1H), 3.60 (m, 2H), 2.90 (m, 2H), 2.75(s, 3H), 1.90 (s, 3H), 1.40 (d, 3H).

Example 106 Preparation of Compound 128

6-chloro-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (248mg, 1.00 mmol) was dissolved in toluene (4 mL) and K₂CO₃ (276 mg, 0.2mmol), CuSO₄.5H₂O (249 mg, 0.01 mmol) and 1,10-phenanthroline (36 mg,0.2 mmol) were added to it. The reaction mixture was stirred for 10 minand a solution of 1-(bromoethynyl)-4-fluorobenzene (220 mg, 1.1 mmol) intoluene (2 mL) was added. The reaction mixture was purged with nitrogenand heated at 80-85° C. for 12 h. Solvent was evaporated under reducedpressure and the residue was purified by silica gel chromatography(100-200 mesh) using 0-3% Methanol: DCM as eluent followed by reversephase chromatography. ¹H NMR (CDCl₃) TFA SALT 7.50 (m, 4H), 7.35 (d,1H), 7.10 (m, 2H), 4.60 (m, 1H), 3.70 (m, 1H), 3.60 (m, 1H), 3.10 (m,1H), 3.0 (s, 3H), 2.95 (m, 1H), 1.90 (d, 3H).

Example 107 Preparation of Compound 130

2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200 mg, 1 mmol)was mixed with CuSO₄.5H₂O (50 mg, 0.2 mmol), 1,10-phenanthroline (72 mg,0.4 mmol), K₃PO₄ (425 mg, 2 mmol) and 1-(bromoethynyl)-4-chlorobenzene(237 mg, 1.1 mmol) in toluene (8-10 ml). The reaction mixture wasflushed with nitrogen and heated at 80° C. for 16 h. The reactionmixture was filtered through Celite, and the Celite bed was rinsed withdichloromethane. Combined organic layer was concentrated under reducedpressure and the residue was purified by silica gel chromatography(100-200 mesh) eluting with 60-80% ethyl acetate in hexane to obtain9-((4-chlorophenyl)ethynyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(24 mg) as brown semi solid. ¹H NMR (CDCl₃) FREE BASE 7.42 (m, 3H), 7.36(m, 3H), 7.10 (d, 1H), 3.70 (s, 2H), 2.80 (m, 4H), 2.60 (s, 3H), 2.42(s, 3H).

Example 108 Preparation of Compound 132

6-chloro-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (220 mg,μmol) was mixed with CuSO₄.5H₂O (50 mg, 0.2 mmol), 1,10-phenanthroline(72 mg, 0.4 mmol), K₃PO₄ (425 mg, 2 mmol) and1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (8-10ml). The reaction mixture was flushed with nitrogen and heated at 80° C.for 16 h. The reaction mixture was filtered through Celite and Celitebed was rinsed with dichloromethane. Combined organic layer wasconcentrated under reduced pressure and the residue was purified bysilica gel chromatography (100-200 mesh) eluting with 60-80% ethylacetate in hexane to obtain6-chloro-9-((4-chlorophenyl)ethynyl)-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoleas brown semi solid (88 mg). ¹H NMR (CDCl₃) FREE BASE 7.51-7.43 (m, 4H),7.39-7.36 (d, 1H), 7.30-7.22 (m, 2H), 4.05-3.97 (q, 1H), 3.24-2.80 (m,4H), 2.60 (s, 3H), 1.68-1.58 (d, 3H).

Example 109 Preparation of Compound 155

6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (100 mg,0.45 mmol) was mixed with CuSO₄.5H₂O (23 mg, 0.090 mmol),1,10-phenanthroline (33 mg, 0.18 mmol), K₃PO₄ (192 mg, 0.90 mmol) and4-(bromoethynyl)-2-fluoro-1-methoxybenzene (113 mg, 0.49 mmol) intoluene (5 ml). The reaction mixture was purged with nitrogen and heatedat 80° C. for 16 h. Product was detected by LCMS. The reaction mixturewas filtered through Celite and Celite bed was rinsed withdichloromethane. Combined organic layer was concentrated under reducedpressure and the residue was purified by silica gel chromatography(100-200 mesh) eluting with 60-80% ethyl acetate in hexane to obtain6-chloro-9-((3-fluoro-4-methoxyphenyl)ethynyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(30 mg). ¹H NMR (CDCl₃) FREE BASE 7.42 (d, 2H), 7.25 (m, 3H), 6.95 (t,1H), 3.90 (s, 3H), 3.70 (s, 2H), 2.80 (m, 4H), 2.56 (s, 3H).

Example 110 Preparation of Compound 97

2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (72 mg, 0.362mmol) was dissolved in DMF (5 mL). To this solution was added CuI (6 mg,0.0362 mmol), L-proline (8 mg, 0.072 mmol), and K₃PO₄ (154 mg, 0.724mmol). The reaction mixture was stirred for 10 min at room temperaturefollowed by addition of 1-(1-bromoprop-1-en-2-yl)-4-chlorobenzene (100mg, 0.434 mmol). The reaction mixture was heated at 80° C. overnight.Solvent was evaporated under reduced pressure, the residue was dilutedwith brine and extracted with ethyl acetate. Organic layer was driedover Na₂SO₄, and concentrated under reduced pressure. The crude productwas purified by silica gel chromatography to obtain 85 mg of9-(2-(4-chlorophenyl)prop-1-enyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (CDCl₃) FREE BASE 7.48 (d, 1H), 7.39 (d, 1H), 7.29 (s, 1H),7.18-7.10 (m, 1H), 7.09-7.0 (m, 2H), 6.93 (d, 1H), 6.86 (s, 1H),3.78-3.68 (m, 2H), 3.43-3.35 (m, 1H), 3.16-2.70 (m, 3H), 2.64 (s, 3H),2.47 (s, 3H), 1.99 (s, 3H).

Example 111 Preparation of Compound 98

6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (79 mg, 0.36mmol) was dissolved in DMF (5 mL). To this solution was added CuI (6 mg,0.0362 mmol), L-proline (8 mg, 0.072 mmol), and K₃PO₄ (154 mg, 0.724mmol). The reaction mixture was stirred for 10 min at room temperaturefollowed by addition of 1-(1-bromoprop-1-en-2-yl)-4-chlorobenzene (100mg, 0.434 mmol). The reaction mixture was heated at 80° C. overnight.Solvent was evaporated under reduced pressure, the residue was dilutedwith brine and extracted with ethyl acetate. Organic layer was driedover Na₂SO₄, and concentrated under reduced pressure. The crude productwas purified by silica gel chromatography to obtain 85 mg of6-chloro-9-(2-(4-chlorophenyl)prop-1-enyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (CDCl₃) FREE BASE 7.53-7.44 (m, 2H), 7.43-7.38 (m, 2H), 7.18-7.03(m, 2H), 6.93 (d, 1H), 6.84 (s, 1H), 3.63-3.58 (m, 2H), 3.32-3.26 (m,1H), 2.88 (s, 3H), 2.83-2.80 (m, 1H), 2.60 (s, 2H), 1.99 (s, 3H).

Example 112 Preparation of Compound 99

6-chloro-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (42 mg,0.180 mmol) was dissolved in DMF (3 mL). To this solution was added CuI(3 mg, 0.018 mmol), L-proline (4 mg, 0.036 mmol), K₃PO₄ (77 mg, 0.36mmol). The reaction mixture was stirred for 10 min at room temperaturefollowed by addition of 1-(1-bromoprop-1-en-2-yl)-4-chlorobenzene (50mg, 0.217 mmol). The reaction mixture was heated at 80° C. overnight.Solvent was evaporated under reduced pressure, the residue was dilutedwith brine and extracted with ethyl acetate. Organic layer was driedover Na₂SO₄, and concentrated under reduced pressure. The crude productwas purified by silica gel chromatography to obtain 17 mg, of6-chloro-9-(2-(4-chlorophenyl)prop-1-enyl)-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (CDCl₃) FREE BASE 7.53-7.47 (m, 2H), 7.43-7.38 (m, 2H), 7.15-7.10(m, 1H), 7.06-7.00 (m, 2H), 6.84 (s, 1H), 3.83-3.75 (m, 1H), 3.22-3.10(m, 1H), 2.97-2.83 (m, 2H), 2.73-2.64 (m, 1H), 2.54 (s, 3H), 1.93 (s,3H), 1.73 (d, 3H), 1.28 (s, 3H).

Example 113 Preparation of Compound 100

6-chloro-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (45mg, 0.180 mmol) was dissolved in DMF (3 mL). To this solution was addedCuI (3 mg, 0.018 mmol), L-proline (4 mg, 0.036 mmol), K₃PO₄ (77 mg, 0.36mmol). The reaction mixture was stirred for 10 min at room temperaturefollowed by addition of 1-(1-bromoprop-1-en-2-yl)-4-chlorobenzene (50mg, 0.217 mmol). The reaction mixture was heated at 80° C. overnight.Solvent was evaporated under reduced pressure, the residue was dilutedwith brine and extracted with ethyl acetate. Organic layer was driedover Na₂SO₄, and concentrated under reduced pressure. The crude productwas purified by silica gel chromatography to obtain 18 mg, of6-chloro-9-(2-(4-chlorophenyl)prop-1-enyl)-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole¹H NMR (CDCl₃) FREE BASE 7.53-7.40 (m, 4H), 7.19-7.10 (m, 2H), 7.03 (d,1H), 6.85 (s, 1H), 3.55-3.48 (m, 1H), 3.35-3.20 (m, 2H), 3.10-2.83 (m,2H), 2.60 (s, 3H), 1.93 (s, 3H), 1.88-1.75 (m, 2H), 1.03 (t, 3H).

Example 114 Preparation of Compound 108

6-chloro-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (150mg, 0.604 mmol) was dissolved in DMF (4 mL). To this solution was addedCuI (11 mg, 0.06 mmol), L-proline (14 mg, 0.12 mmol), K₃PO₄ (257 mg, 1.2mmol). The reaction mixture was stirred for 10 min at room temperaturefollowed by addition of 3-(1-bromoprop-1-en-2-yl)pyridine (143 mg, 0.725mmol). The reaction mixture was heated at 80° C. overnight. Solvent wasevaporated under reduced pressure; the residue was diluted with brineand extracted with ethyl acetate. Organic layer was dried over Na₂SO₄,and concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography to obtain 70 mg of title compound. ¹H NMR(CD₃OD) TFA SALT 9.10 (s, 1H), 8.80 (s, 1H), 8.62 (d, 1H), 7.95 (s, 1H),7.60 (s, 1H), 7.40 (s, 1H), 7.22 (m, 2H), 4.70 (m, 1H), 3.80 (m, 1H),3.60 (m, 1H), 3.20 (m, 2H), 3.05 (s, 3H), 2.18 (m, 2H), 2.05 (s, 3H),1.10 (t, 3H).

Example 115 Preparation of Compound 113

2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (63 mg, 0.31mmol) was dissolved in DMF (5 mL). To this solution was added CuI (6 mg,0.032 mmol), L-proline (7 mg, 0.063 mmol), K₃PO₄ (134 mg, 0.63 mmol).The reaction mixture was stirred for 10 min at room temperature followedby addition of 4-(1-bromoprop-1-en-2-yl)-1,2-dichlorobenzene (100 mg,0.378 mmol). The reaction mixture was heated at 80° C. overnight.Solvent was evaporated under reduced pressure, the residue was dilutedwith brine and extracted with ethyl acetate. Organic layer was driedover Na₂SO₄, and concentrated under reduced pressure. The crude productwas purified by silica gel chromatography to obtain 45 mg of9-(2-(3,4-dichlorophenyl)prop-1-enyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (CD₃OD) TFA SALT 7.82 (d, 1H), 7.58 (d, 2H), 7.36 (d, 1H), 7.15(m, 2H), 7.0 (s, 1H), 4.65 (m, 1H), 4.40 (m, 1H), 3.85 (m, 1H), 3.60 (m,1H), 3.20 (m, 2H), 3.10 (s, 3H), 2.42 (s, 3H), 2.0 (s, 3H).

Example 116 Preparation of Compound 106

6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200 mg, 0.9mmol) was dissolved in DMF (5 mL). To this solution was added CuI (17mg, 0.09 mmol), L-proline (20 mg, 0.18 mmol), K₃PO₄ (387 mg, 1.8 mmol).The reaction mixture was stirred for 10 min at room temperature followedby addition of 3-(1-bromoprop-1-en-2-yl)pyridine (215 mg, 1.09 mmol).The reaction mixture was heated at 90° C. overnight. Solvent wasevaporated under reduced pressure, the residue was diluted with brineand extracted with ethyl acetate. Organic layer was dried over Na₂SO₄,and concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography to obtain 180 mg of title compound. ¹H NMR(CD₃OD) TFA SALT 9.10 (m, 1H), 8.80 (m, 1H), 8.50 (d, 1H), 7.82 (s, 1H),7.60 (s, 1H), 7.30 (m, 3H), 4.60 (m, 2H), 3.70 (m, 2H), 3.20 (m, 2H),3.15 (s, 3H), 2.05 (s, 3H).

Example 117 Preparation of Compound 107

6-chloro-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (100 mg,0.42 mmol) was dissolved in DMF (4 mL). To this solution was added CuI(8 mg, 0.04 mmol), L-proline (9 mg, 0.08 mmol), K₃PO₄ (182 mg, 0.85mmol). The reaction mixture was stirred for 10 min at room temperaturefollowed by addition of 3-(1-bromoprop-1-en-2-yl)pyridine (101 mg, 0.51mmol). The reaction mixture was heated at 90° C. for 18 h. Solvent wasevaporated under reduced pressure, the residue was diluted with brineand extracted with ethyl acetate. Organic layer was dried over Na₂SO₄,and concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography to obtain 80 mg of title compound. MS m/zobserved 352 (M+1).

Example 118 Preparation of Compound 117

2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (73 mg, 0.36mmol) was dissolved in DMF (6 mL). To this solution was added CuI (7 mg,0.036 mmol), L-proline (8 mg, 0.073 mmol), K₃PO₄ (156 mg, 0.734 mmol).The reaction mixture was stirred for 10 min at room temperature followedby addition of 1-(1-bromoprop-1-en-2-yl)-4-methoxybenzene (100 mg, 0.44mmol). The reaction mixture was heated at 80° C. for 18 h. Solvent wasevaporated under reduced pressure, the residue was diluted with brineand extracted with ethyl acetate. Organic layer was dried over Na₂SO₄,and concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography to obtain 22 mg of9-(2-(4-methoxyphenyl)prop-1-enyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (DMSO) OXALATE SALT 7.60 (d, 2H), 7.30 (d, 1H), 7.10 (d, 1H), 7.0(m, 4H), 4.20 (m, 2H), 3.80 (s, 3H), 3.40 (m, 2H), 2.95 (m, 2H), 2.82(s, 3H), 2.40 (s, 3H), 1.82 (s, 3H).

Example 119 Preparation of Compound 118

6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (80 mg, 0.36mmol) was dissolved in DMF (6 mL). To this solution was added CuI (7 mg,0.036 mmol), L-proline (8 mg, 0.073 mmol), K₃PO₄ (156 mg, 0.734 mmol).The reaction mixture was stirred for 10 min at room temperature followedby addition of 1-(1-bromoprop-1-en-2-yl)-4-methoxybenzene (100 mg, 0.44mmol). The reaction mixture was heated at 80° C. for 18 h. Solvent wasevaporated under reduced pressure, the residue was diluted with brineand extracted with ethyl acetate. Organic layer was dried over Na₂SO₄,and concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography to obtain 67 mg of6-chloro-9-(2-(4-methoxyphenyl)prop-1-enyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (DMSO) OXALATE SALT 7.60 (m, 3H), 7.25 (d, 1H), 7.18 (d, 1H), 7.0(m, 3H), 4.20 (m, 2H), 3.80 (s, 3H), 3.38 (m, 2H), 2.95 (m, 2H), 2.80(s, 3H), 1.82 (s, 3H).

Example 120 Preparation of Compound 119

6-chloro-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (85 mg,0.36 mmol) was dissolved in DMF (6 mL). To this solution was added CuI(7 mg, 0.036 mmol), L-proline (8 mg, 0.073 mmol), K₃PO₄ (156 mg, 0.734mmol). The reaction mixture was stirred for 10 min at room temperaturefollowed by addition of 1-(1-bromoprop-1-en-2-yl)-4-methoxybenzene (100mg, 0.44 mmol). The reaction mixture was heated at 80° C. for 18 h.Solvent was evaporated under reduced pressure, the residue was dilutedwith brine and extracted with ethyl acetate. Organic layer was driedover Na₂SO₄, and concentrated under reduced pressure. The crude productwas purified by silica gel chromatography to obtain 18 mg of6-chloro-9-(2-(4-methoxyphenyl)prop-1-enyl)-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (DMSO) OXALATE SALT 7.60 (m, 3H), 7.18 (s, 2H), 7.05 (s, 1H), 7.0(d, 2H), 3.80 (s, 3H), 3.50 (m, 2H), 2.85 (m, 4H), 2.70 (m, 2H), 1.80(s, 3H), 1.20 (d, 3H).

Example 121 Preparation of Compound 120

6-chloro-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (91mg, 0.36 mmol) was dissolved in DMF (5 mL). To this solution was addedCuI (7 mg, 0.036 mmol), L-proline (8 mg, 0.073 mmol), K₃PO₄ (156 mg,0.734 mmol). The reaction mixture was stirred for 10 min at roomtemperature followed by addition of1-(1-bromoprop-1-en-2-yl)-4-methoxybenzene (100 mg, 0.44 mmol). Thereaction mixture was heated at 80° C. for 18 h. Solvent was evaporatedunder reduced pressure, the residue was diluted with brine and extractedwith ethyl acetate. Organic layer was dried over Na₂SO₄, andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography to obtain 12 mg of6-chloro-1-ethyl-9-(2-(4-methoxyphenyl)prop-1-enyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (DMSO) OXALATE SALT 7.60 (m, 3H), 7.18 (s, 2H), 7.05 (s, 1H), 7.0(d, 2H), 3.80 (s, 3H), 3.70 (m, 1H), 2.90 (m, 4H), 2.70 (m, 3H), 1.80(m, 5H), 0.95 (t, 3H).

Example 122 Preparation of Compound 123

6-chloro-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (80 mg,0.34 mmol) was dissolved in DMF (6 mL). To this solution was added CuI(6 mg, 0.034 mmol), L-proline (8 mg, 0.068 mmol), K₃PO₄ (145 mg, 0.68mmol). The reaction mixture was stirred for 10 min at room temperaturefollowed by addition of4-(1-bromoprop-1-en-2-yl)-2-fluoro-1-methoxybenzene (100 mg, 0.40 mmol).The reaction mixture was heated at 80° C. for 18 h. Solvent wasevaporated under reduced pressure, the residue was diluted with brineand extracted with ethyl acetate. Organic layer was dried over Na₂SO₄,and concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography to obtain 17 mg of6-chloro-9-(2-(3-fluoro-4-methoxyphenyl)prop-1-enyl)-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (DMSO) OXALATE SALT 7.65 (d, 2H), 7.47 (dd, 1H), 7.25 (d, 2H),7.20 (s, 1H), 7.12 (s, 1H), 3.90 (s, 3H), 3.40 (m, 3H), 2.96 (m, 2H),2.80 (s, 3H), 1.80 (s, 3H), 1.50 (d, 3H).

Example 123 Preparation of Compound 124

6-chloro-1-ethyl-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (84mg, 0.34 mmol) was dissolved in DMF (5 mL). To this solution was addedCuI (6 mg, 0.034 mmol), L-proline (8 mg, 0.068 mmol), K₃PO₄ (145 mg,0.68 mmol). The reaction mixture was stirred for 10 min at roomtemperature followed by addition of4-(1-bromoprop-1-en-2-yl)-2-fluoro-1-methoxybenzene (100 mg, 0.408mmol). The reaction mixture was heated at 80° C. for 18 h. Solvent wasevaporated under reduced pressure, the residue was diluted with brineand extracted with ethyl acetate. Organic layer was dried over Na₂SO₄,and concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography to obtain 21 mg of6-chloro-1-ethyl-9-(2-(3-fluoro-4-methoxyphenyl)prop-1-enyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (CD₃OD) TFA SALT 7.60 (d, 1H), 7.42 (m, 2H), 7.20 (m, 3H), 7.0(s, 1H), 4.60 (m, 1H), 3.90 (s, 3H), 3.8 (m, 1H), 3.60 (m, 1H), 3.20 (m,2H), 3.05 (s, 3H), 2.10 (m, 2H), 1.90 (s, 3H), 1.10 (t, 3H).

Example 124 Preparation of Compound 159

1-Ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (228 mg,1 mmol) was mixed with CuSO₄.5H₂O (249 mg, 1 mmol), 1,10-phenanthroline(36 mg, 0.2 mmol), K₂CO₃ (276 mg, 0.2 mmol) and1-(bromoethynyl)-4-fluorobenzene compound (220 mg, 1.1 mmol) in toluene(8-10 ml). The reaction mixture was flushed with nitrogen and heated at80-85° C. for 16 h. The reaction mixture was filtered through Celite,and the Celite bed was rinsed with dichloromethane. Combined organiclayer was concentrated under reduced pressure and the residue waspurified by silica gel chromatography (100-200 mesh) eluting with 5%MeOH/DCM as eluent followed by reverse phase chromatography. ¹H NMR(CD₃OD) TFA SALT 7.80 (d, 1H), 7.40 (d, 1H), 7.30 (m, 3H), 7.05 (m, 2H),5.0 (m, 1H), 4.50 (m, 2H), 3.80 (m, 1H), 3.55 (m, 1H), 3.10 (m, 2H), 3.0(s, 3H), 2.42 (s, 3H), 1.80 (q, 2H), 1.18 (t, 3H).

Example 125 Preparation of Compound 160

1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (42 mg,0.180 mmol) was dissolved in DMF (4 mL). To this solution was added CuI(3 mg, 0.0180 mmol), L-proline (4 mg, 0.036 mmol), K₃PO₄ (77 mg, 0.360mmol). The reaction mixture was stirred for 10 min at room temperaturefollowed by addition of 1-(1-bromoprop-1-en-2-yl)-4-chlorobenzene (50mg, 0.217 mmol). The reaction mixture was heated at 80° C. for 18 h.Solvent was evaporated under reduced pressure, the residue was dilutedwith brine and extracted with ethyl acetate. Organic layer was driedover Na₂SO₄, and concentrated under reduced pressure. The crude productwas purified by silica gel chromatography to obtain 20 mg, of9-(2-(4-chlorophenyl)prop-1-enyl)-1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (CDCl₃) FREE BASE-7.5 (d, 2H), 7.4 (d, 2H), 7.33 (s, 1H), 7.02(s, 2H), 6.85 (s, 1H), 3.40-3.24 (m, 1H), 3.14-2.90 (m, 1H), 2.82-2.7(m, 1H), 2.68-2.53 (m, 2H), 2.43 (s, 3H), 2.06-2.02 (m, 1H), 1.93 (s,3H), 1.90-1.72 (m, 1H), 1.30 (s, 3H), 1.1-0.98 (m, 3H).

Example 126 Preparation of Compound 161

1,2,6-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (39 mg, 0.180mmol) was dissolved in DMF (4 mL). To this solution was added CuI (3 mg,0.0180 mmol), L-proline (4 mg, 0.036 mmol), K₃PO₄ (77 mg, 0.360 mmol).The reaction mixture was stirred for 10 min at room temperature followedby addition of 1-(1-bromoprop-1-en-2-yl)-4-chlorobenzene (50 mg, 0.217mmol). The reaction mixture was heated at 80° C. for 18 h. Solvent wasevaporated under reduced pressure, the residue was diluted with brineand extracted with ethyl acetate. Organic layer was dried over Na₂SO₄,and concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography to obtain 25 mg, of9-(2-(4-chlorophenyl)prop-1-enyl)-1,2,6-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (CDCl₃) FREE BASE-7.48 (d, 2H), 7.4 (d, 2H), 7.32 (s, 1H), 7.04(s, 2H), 6.87 (s, 1H), 4.03-3.94 (m, 1H), 3.4-3.3 (m, 1H), 3.18-3.08 (m,1H), 2.9-2.8 (m, 1H), 2.72-2.63 (m, 1H), 2.48 (s, 3H), 1.95 (s, 3H),1.33-1.20 (m, 6H).

Example 127 Preparation of Compound 162

1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (228 mg,μmol) was mixed with CuSO₄.5H₂O (50 mg, 0.2 mmol), 1,10-phenanthroline(72 mg, 0.4 mmol), K₃PO₄ (425 mg, 2 mmol) and1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (8-10ml). The reaction mixture was flushed with nitrogen and heated at 80° C.for 16 h. The reaction mixture was filtered through Celite, and theCelite bed was rinsed with dichloromethane. Combined organic layer wasconcentrated under reduced pressure and the residue was purified bysilica gel chromatography (100-200 mesh) eluting with 60-80% ethylacetate in hexane to obtain9-((4-chlorophenyl)ethynyl)-1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoleas brown semi solid (30 mg). ¹H NMR (CDCl₃) FREE BASE 7.50-7.40 (m, 3H),7.37-7.33 (m, 2H), 7.28 (s, 1H), 7.20-7.15 (d, 1H), 5.25-5.20 (t, 1H),3.06 (s, 3H), 3.02 (s, 3H), 2.98-2.88 (m, 2H), 2.80-2.60 (m, 2H),1.20-1.18 (m, 2H), 1.10-1.07 (t, 3H).

Example 128 Preparation of Compound 163

2,6-dimethyl-1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (276 mg,μmol) was mixed with CuSO₄.5H₂O (50 mg, 0.2 mmol), 1,10-phenanthroline(72 mg, 0.4 mmol), K₃PO₄ (425 mg, 2 mmol) and1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (8-10ml). The reaction mixture was flushed with nitrogen and heated at 80° C.for 16 h. The reaction mixture was filtered through Celite, and theCelite bed was rinsed with dichloromethane. Combined organic layer wasconcentrated under reduced pressure and the residue was purified bysilica gel chromatography (100-200 mesh) eluting with 60-80% ethylacetate in hexane to obtain9-((4-chlorophenyl)ethynyl)-1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoleas brown semi solid (90 mg). The product was dissolved in 50% aqueousTFA:acetonitrile (1:1) and stirred at 50° C. to obtain the titlecompound as TFA salt (off white solid). ¹H NMR (CD₃OD) TFA SALT 7.65 (d,1H), 7.45-7.3 (m, 4H), 7.2 (m, 3H), 7.05 (m, 2H), 6.7 (d, 2H), 6.25 (s,1H), 4.25 (d, 1H), 4.15 (d, 1H), 3.4 (m, 2H), 3.2 (m, 2H), 2.9 (bs, 3),2.4 (s, 3H).

Example 129 Preparation of Compound 164

2,6-dimethyl-1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (99 mg,0.362 mmol) was dissolved in DMF (5 mL). To this solution was added CuI(6 mg, 0.0362 mmol), L-proline (8 mg, 0.072 mmol), K₃PO₄ (154 mg, 0.724mmol). The reaction mixture was stirred for 10 min at room temperaturefollowed by addition of 1-(1-bromoprop-1-en-2-yl)-4-chlorobenzene (100mg, 0.434 mmol). The reaction mixture was heated at 80° C. for 18 h.Solvent was evaporated under reduced pressure, the residue was dilutedwith brine and extracted with ethyl acetate. Organic layer was driedover Na₂SO₄, and concentrated under reduced pressure. The crude productwas purified by silica gel chromatography to obtain 35 mg, of9-(2-(4-chlorophenyl)prop-1-enyl)-2,6-dimethyl-1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (CDCl₃) TFA SALT-7.42 (s, 1H), 7.25-7.2 (m, 5H), 7.2-7.16 (m,2H), 7.10-7.0 (m, 3H), 6.96 (d, 1H), 6.2 (s, 1H), 4.45 (bs, 1H),3.22-3.28 (m, 1H), 3.17-3.08 (m, 4H), 2.9-2.8 (m, 1H), 2.5 (s, 3H),2.45-2.4 (m, 4H).

Example 130 Preparation of Compound 165

1,2,6-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (213 mg, 1mmol) was dissolved in DMF (5 mL). To this solution was added CuI (19mg, 0.1 mmol), L-proline (0.2 mmol), K₃PO₄ (424 mg, 2 mmol). Thereaction mixture was stirred for 10 min at room temperature followed byaddition of 1-(1-bromoprop-1-en-2-yl)-2-fluorobenzene (260 mg, 1.2mmol). The reaction mixture was heated at 85° C. for 18 h. Solvent wasevaporated under reduced pressure, the residue was diluted with brineand extracted with ethyl acetate. Organic layer was dried over Na₂SO₄,and concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography followed by reverse phase chromatography.¹H NMR (CDCl₃) TFA SALT 7.25-7.00 (m, 4H), 6.90 (m, 2H), 6.70 (s, 1H),4.05 (m, 1H), 3.60 (m, 1H), 3.40 (m, 1H), 3.0 (m, 3H), 2.45 (s, 3H),2.30 (s, 3H), 2.22 (s, 3H), 1.60 (d, 3H).

Example 131 Preparation of Compound 166

1,2,6-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (213 mg, 1mmol) was dissolved in DMF (5 mL). To this solution was added CuI (19mg, 0.1 mmol), L-proline (0.2 mmol), K₃PO₄ (424 mg, 2 mmol). Thereaction mixture was stirred for 10 min at room temperature followed byaddition of 1-(1-bromoprop-1-en-2-yl)-2-fluorobenzene (260 mg, 1.2mmol). The reaction mixture was heated at 85° C. for 18 h. Solvent wasevaporated under reduced pressure, the residue was diluted with brineand extracted with ethyl acetate. Organic layer was dried over Na₂SO₄,and concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography followed by reverse phase chromatography.¹H NMR (CDCl₃) TFA SALT 7.40 (m, 3H), 7.20 (m, 4H), 6.70 (s, 1H), 4.42(m, 1H), 3.70 (m, 1H), 3.60 (m, 1H), 3.10 (m, 2H), 3.0 (s, 3H), 2.42 (s,3H), 1.90 (s, 3H), 1.70 (d, 3H).

Example 132 Preparation of Compound 167

6-chloro-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (213 mg,1 mmol) was dissolved in DMF (5 mL). To this solution was added CuI (19mg, 0.1 mmol), L-proline (0.2 mmol), K₃PO₄ (424 mg, 2 mmol). Thereaction mixture was stirred for 10 min at room temperature followed byaddition of 1-(1-bromoprop-1-en-2-yl)-2-fluorobenzene (260 mg, 1.2mmol). The reaction mixture was heated at 85° C. for 18 h. Solvent wasevaporated under reduced pressure, the residue was diluted with brineand extracted with ethyl acetate. Organic layer was dried over Na₂SO₄,and concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography followed by reverse phase chromatography.¹H NMR (CDCl₃) TFA SALT 7.40 (s, 1H), 7.15 (m, 3H), 6.95-6.80 (m, 3H),6.70 (s, 1H), 4.10 (m, 1H), 3.58 (m, 1H), 3.40 (m, 1H), 2.80 (m, 2H),2.42 (s, 3H), 2.30 (s, 3H), 1.65 (d, 3H).

Example 133 Preparation of Compound 168

6-chloro-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (213 mg,1 mmol) was dissolved in DMF (5 mL). To this solution was added CuI (19mg, 0.1 mmol), L-proline (0.2 mmol), K₃PO₄ (424 mg, 2 mmol). Thereaction mixture was stirred for 10 min at room temperature followed byaddition of 1-(1-bromoprop-1-en-2-yl)-2-fluorobenzene (260 mg, 1.2mmol). The reaction mixture was heated at 85° C. for 18 h. Solvent wasevaporated under reduced pressure, the residue was diluted with brineand extracted with ethyl acetate. Organic layer was dried over Na₂SO₄,and concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography followed by reverse phase chromatography.¹H NMR (CDCl₃) TFA SALT 7.55 (s, 1H), 7.38 (m, 2H), 7.22-7.10 (m, 4H),6.70 (s, 1H), 4.55 (m, 1H), 3.70 (m, 1H), 3.60 (m, 1H), 3.10 (m, 2H),3.0 (s, 3H), 2.0 (s, 3H), 1.78 (d, 3H).

Example 134 Preparation of Compound 169

1,2,6-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (235 mg, 1mmol) was dissolved in DMF (5 mL). To this solution was added CuI (19mg, 0.1 mmol), L-proline (0.2 mmol), K₃PO₄ (424 mg, 2 mmol). Thereaction mixture was stirred for 10 min at room temperature followed byaddition of 1-(1-bromoprop-1-en-2-yl)-2,4-dichlorobenzene (318 mg, 1.2mmol). The reaction mixture was heated at 85° C. for 18 h. Solvent wasevaporated under reduced pressure; the residue was diluted with brineand extracted with ethyl acetate. Organic layer was dried over Na₂SO₄,and concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography followed by reverse phase chromatography.¹H NMR (CDCl₃) TFA SALT 7.38 (s, 1H), 7.20 (m, 2H), 7.10 (d, 1H), 6.98(d, 1H), 7.82 (d, 1H), 6.70 (s, 1H), 4.25 (m, 1H), 3.60 (m, 1H), 3.40(m, 1H), 2.90 (m, 2H), 2.60 (s, 3H), 2.42 (s, 3H), 2.30 (s, 3H), 1.70(d, 3H).

Example 135 Preparation of Compound 170

1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (235 mg,1 mmol) was dissolved in DMF (5 mL). To this solution was added CuI (19mg, 0.1 mmol), L-proline (0.2 mmol), K₃PO₄ (424 mg, 2 mmol). Thereaction mixture was stirred for 10 min at room temperature followed byaddition of 1-(1-bromoprop-1-en-2-yl)-2,4-dichlorobenzene (318 mg, 1.2mmol). The reaction mixture was heated at 85° C. for 18 h. Solvent wasevaporated under reduced pressure, the residue was diluted with brineand extracted with ethyl acetate. Organic layer was dried over Na₂SO₄,and concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography followed by reverse phase chromatography.¹H NMR (CD₃OD) TFA SALT 7.62 (s, 1H), 7.55 (d, 1H), 7.45 (d, 1H), 7.40(s, 1H), 7.30 (d, 1H), 7.18 (d, 1H), 6.70 (s, 1H), 4.60 (m, 1H), 3.80(m, 1H), 3.60 (m, 1H), 3.20 (m, 2H), 3.0 (s, 3H), 2.42 (s, 3H), 2.20 (m,2H), 1.90 (s, 3H), 1.20 (t, 3H).

Example 136 Preparation of Compound 171

6-chloro-1-ethyl-9-((4-fluorophenyl)ethynyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(50 mg) was dissolved in acetonitrile and water (1:1, 5 mL) followed byaddition of TFA (0.1 mL). The reaction mixture was heated at 55° C. for1 h. Solvent was evaporated under reduced pressure and the residue wasbasified with 10% KOH solution and extracted in DCM. Organic layer waswashed with water, dried over anhydrous sodium sulphate andconcentrated. The residue was purified by silica gel chromatography(100-200 mesh) using 0-1% methanol: DCM as eluant followed by reversephase chromatography. ¹H NMR (CD₃OD) TFA SALT 7.90 (d, 1H), 7.50 (s,1H), 7.30 (m, 3H), 7.05 (t, 2H), 4.50 (m, 2H), 4.10 (m, 1H), 3.25 (m,1H), 2.90 (m, 2H), 2.58 (m, 1H), 2.42 (s, 3H), 1.78 (m, 1H), 1.60 (m,1H), 1.05 (t, 3H).

Example 137 Preparation of Compound 172

1,2,6-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (214 mg, μmol)was mixed with CuSO₄.5H₂O (50 mg, 0.2 mmol), 1,10-phenanthroline (72 mg,0.4 mmol), K₃PO₄ (425 mg, 2 mmol) and 1-(bromoethynyl)-4-chlorobenzene(237 mg, 1.1 mmol) in toluene (8-10 ml). The reaction mixture wasflushed with nitrogen and heated at 80° C. for 16 h. The reactionmixture was filtered through Celite, and the Celite bed was rinsed withdichloromethane. Combined organic layer was concentrated under reducedpressure and the residue was purified by silica gel chromatography(100-200 mesh) eluting with 60-80% ethyl acetate in hexane to obtain9-((4-chlorophenyl)ethynyl)-1,2,6-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(67 mg) as brown semi solid. ¹H NMR (CDCl₃) FREE BASE 7.42 (d, 2H), 7.38(d, 2H), 7.30 (m, 2H), 7.10 (d, 1H), 3.90 (m, 1H), 3.20 (m, 1H), 2.90(m, 2H), 2.62 (m, 1H), 2.58 (s, 3H), 2.42 (s, 3H), 1.30 (d, 3H).

Example 138 Preparation of Compound 173

9-((4-chlorophenyl)ethynyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(50 mg) was dissolved in acetonitrile and water (1:1, 5 mL) followed byaddition of TFA (0.1 mL). The reaction mixture was heated at 55° C. for1 h. Solvent was evaporated under reduced pressure and the residue wasbasified with 10% KOH solution and extracted in DCM. Organic layer waswashed with water, dried over anhydrous sodium sulphate andconcentrated. The residue was purified by silica gel chromatography(100-200 mesh) using 0-1% methanol: DCM as eluant followed by reversephase chromatography. TFA SALT-BATCH1 ¹H NMR (CDCl₃) TFA SALT 7.60 (d,1H), 7.36 (d, 2H), 7.30 (s, 1H), 7.22 (m, 3H), 5.0 (m, 1H), 4.35 (m,3H), 3.90 (m, 1H), 3.30 (m, 1H), 3.15 (m, 1H), 3.05 (s, 3H), 2.95 (m,1H), 2.45 (s, 3H).

Example 139 Preparation of Compound 174

1,2,6-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (67 mg, 0.31mmol) was dissolved in DMF (5 mL). To this solution was added CuI (6 mg,0.032 mmol), L-proline (7 mg, 0.063 mmol), K₃PO₄ (134 mg, 0.63 mmol).The reaction mixture was stirred for 10 min at room temperature followedby addition of 4-(1-bromoprop-1-en-2-yl)-1,2-dichlorobenzene (100 mg,0.378 mmol). The reaction mixture was heated at 80° C. for 18 h. Solventwas evaporated under reduced pressure, the residue was diluted withbrine and extracted with ethyl acetate. Organic layer was dried overNa₂SO₄, and concentrated under reduced pressure. The crude product waspurified by silica gel chromatography followed by reverse phasechromatography to afford 70 mg of9-(2-(3,4-difluorophenyl)prop-1-enyl)-1,2,6-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR FREE BASE (CDCl₃): 7.62 (s, 1H), 7.48 (d, 1H), 7.40 (dd, 1H),7.33 (s, 1H), 7.08-7.0 (m, 2H), 6.90 (s, 1H), 3.83-3.78 (m, 1H),3.25-3.15 (m, 1H), 2.98-2.90 (m, 2H), 2.73-2.68 (m, 1H), 2.58 (s, 3H),2.45 (s, 3H), 1.98 (s, 3H), 1.38 (d, 3H).

Example 140 Preparation of Compound 175

1,2,6-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (77 mg, 0.359mmol) was dissolved in DMF (5 mL). To this solution was added CuI (8 mg,0.0359 mmol), L-proline (9 mg, 0.086 mmol), K₃PO₄ (183 mg, 0.862 mmol).The reaction mixture was stirred for 10 min at room temperature followedby addition of 4-(1-bromoprop-1-en-2-yl)-1,2-difluorobenzene (100 mg,0.431 mmol). The reaction mixture was heated at 80° C. for 18 h. Solventwas evaporated under reduced pressure, the residue was diluted withbrine and extracted with ethyl acetate. Organic layer was dried overNa₂SO₄, and concentrated under reduced pressure. The crude product waspurified by silica gel chromatography 5 mg of9-(2-(3,4-difluorophenyl)prop-1-enyl)-1,2,6-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (CDCl₃) FREE BASE7.38 (m, 2H), 7.20 (m, 2H), 7.0 (d, 2H), 6.80(s, 1H), 3.80 (m, 1H), 3.20 (m, 1H), 2.90 (m, 2H), 2.70 (m, 1H), 2.60(s, 3H), 2.42 (s, 3H), 1.90 (s, 3H), 1.30 (d, 3H).

Example 141 Preparation of Compound 176

1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (82 mg,0.36 mmol) was dissolved in DMF (6 mL). To this solution was added CuI(8 mg, 0.036 mmol), L-proline (9 mg, 0.086 mmol), K₃PO₄ (183 mg, 0.86mmol). The reaction mixture was stirred for 10 min at room temperaturefollowed by addition of 4-(1-bromoprop-1-en-2-yl)-1,2-difluorobenzene(100 mg, 0.43 mmol). The reaction mixture was heated at 80° C. for 18 h.Solvent was evaporated under reduced pressure, the residue was dilutedwith brine and extracted with ethyl acetate. Organic layer was driedover Na₂SO₄, and concentrated under reduced pressure. The crude productwas purified by silica gel chromatography to obtain 25 mg of(E)-9-(2-(3,4-difluorophenyl)prop-1-enyl)-1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR (DMSO) OXALATE SALT 7.80 (m, 1H), 7.56 (m, 2H), 7.38 (s, 1H),7.20 (s, 1H), 7.05 (m, 2H), 3.80 (m, 3H), 3.18 (s, 3H), 3.0 (m, 2H),2.80 (m, 2H), 2.40 (s, 3H), 1.82 (s, 3H), 0.95 (t, 3H).

Example 142 Preparation of Compound 177

1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (72 mg,0.31 mmol) was dissolved in DMF (5 mL). To this solution was added CuI(6 mg, 0.032 mmol), L-proline (7 mg, 0.063 mmol), K₃PO₄ (134 mg, 0.63mmol). The reaction mixture was stirred for 10 min at room temperaturefollowed by addition of 4-(1-bromoprop-1-en-2-yl)-1,2-dichlorobenzene(100 mg, 0.378 mmol). The reaction mixture was heated at 80° C. for 18h. Solvent was evaporated under reduced pressure, the residue wasdiluted with brine and extracted with ethyl acetate. Organic layer wasdried over Na₂SO₄, and concentrated under reduced pressure. The crudeproduct was purified by silica gel chromatography to obtain 70 mg of9-(2-(3,4-dichlorophenyl)prop-1-enyl)-1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.¹H NMR FREE BASE (CDCl₃): 7.63 (s, 1H), 7.49 (d, 1H), 7.39 (d, 1H), 7.34(s, 1H), 7.05-7.0 (m, 2H), 6.94 (s, 1H), 3.44-3.38 (m, 1H), 3.24-3.15(m, 1H), 2.95-2.84 (m, 2H), 2.68-2.6 (m, 1H), 2.53 (s, 2H), 2.46 (s,3H), 1.97 (s, 3H), 1.75-1.65 (m, 2H), 0.98 (t, 3H).

Example 143 Preparation of Compound 178

1,2,6-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (235 mg, 1mmol) was dissolved in DMF (5 mL). To this solution was added CuI (19mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol), K₃PO₄ ((424 mg, 2 mmol). Thereaction mixture was stirred for 10 min at room temperature followed byaddition of 1-(1-bromoprop-1-en-2-yl)-2,4-dichlorobenzene (318 mg, 1.2mmol). The reaction mixture was heated at 85° C. for 18 h. Solvent wasevaporated under reduced pressure; the residue was diluted with brineand extracted with ethyl acetate. Organic layer was dried over Na₂SO₄,and concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography using 0-5% MeOH: DCM as eluant followed byreverse phase chromatography. ¹H NMR (CD₃OD) TFA SALT 7.60 (s, 1H), 7.50(d, 1H), 7.42 (d, 1H), 7.38 (s, 1H), 4.25 (d, 1H), 7.16 (d, 1H), 6.70(s, 1H), 3.85 (m, 1H), 3.60 (m, 2H), 3.18 (m, 2H), 3.05 (s, 3H), 2.42(s, 3H), 1.90 (s, 3H), 1.70 (d, 3H).

Example 144 Preparation of Compound 184

2,6-dimethyl-1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (276 mg,μmol) was mixed with CuSO₄.5H₂O (50 mg, 0.2 mmol), 1,10-phenanthroline(72 mg, 0.4 mmol), K₃PO₄ (425 mg, 2 mmol) and1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (8-10ml). The reaction mixture was flushed with nitrogen and heated at 80° C.for 16 h. The reaction mixture was filtered through Celite, and theCelite bed was rinsed with dichloromethane. Combined organic layer wasconcentrated under reduced pressure and the residue was purified bysilica gel chromatography (100-200 mesh) eluting with 60-80% ethylacetate in hexane to obtain9-((4-chlorophenyl)ethynyl)-1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoleas brown semi solid (90 mg). ¹H NMR (CDCl₃) FREE BASE7.40-7.20 (m, 9H),7.16-7.12 (d, 1H), 7.08-7.04 (d, 2H), 4.73 (s, 1H), 3.22-3.16 (m, 1H),3.0-2.80 (m, 3H), 2.50 (s, 3H), 2.45 (s, 3H).

Example 145 Preparation of Compounds 47, 48, 49, 50, 51, 63, 68, 69, 73,74, 75, 76, 84, 85, 87, 88, 89, 93, 94, 95, 96, 101, 102, 103, 104, 105,126, 127, 131, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143,144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 156, 157, 158,179, 180, 181, 182 and 183.

Compounds 63, 74, 75, 76, 84, 85, 87, 88, 89 and 158 are synthesizedusing appropriate starting materials according to General Methods 1, 3and 4. Compounds 50, 51, 68, 69, 73 and 179 are synthesized usingappropriate starting materials according to General Method 8. Compounds47, 48 and 49 are synthesized using appropriate starting materialsaccording to General Method 9. Compounds 93, 94, 95, 96, 101, 102, 103,104, 105 and 180 are synthesized using appropriate starting materialsaccording to General Method 16. Compounds 126, 127, 131, 133, 134, 135,136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149,150, 151, 152, 153, 154, 156, 157, 181, 182 and 183 are synthesizedusing appropriate starting materials according to General Method 17.

Example B1 Determination of the Ability of Compounds of the Invention toBind a Histamine Receptor Histamine H1

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H1 receptor expressed inChinese hamster ovary (CHO) cells (De Backer, M. D. et al., Biochem.Biophys. Res. Comm. 197(3):1601, 1993) in a modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 2 mM MgCl₂, 100 mM NaCl, 250 mM Sucrose) was used.Compounds of the invention were incubated with 1.2 nM [³H]Pyrilamine for180 minutes at 25° C. Non-specific binding was estimated in the presenceof 1 μM pyrilamine. Receptor proteins were filtered and washed, thefilters were then counted to determine [³H]Pyrilamine specificallybound. Compounds were screened at 1 μM or lower, using 1% DMSO asvehicle. Biochemical assay results are presented as the percentinhibition of specific binding in Table 3.

Histamine H2

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H2 receptor expressed inChinese hamster ovary (CHO) K1 cells (Ruat, M., Proc. Natl. Acad. Sci.USA. 87(5):1658, 1990) in a 50 mM Phosphate buffer, pH 7.4 was used.Compounds of the invention were incubated with 0.1 nM[²⁵I]Aminopotentidine for 120 minutes at 25° C. Non-specific binding wasestimated in the presence of 3 μM Tiotidine. Receptor proteins werefiltered and washed, the filters were then counted to determine[¹²⁵I]Aminopotentidine specifically bound. Compounds were screened at 1μM or lower, using 1% DMSO as vehicle. Biochemical assay results arepresented as the percent inhibition of specific binding in Table 3.

Histamine H3

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H₃ receptor expressed inChinese hamster ovary (CHO-K1) cells (Yanai K et al. Jpn J. Pharmacol.65(2): 107, 1994; Zhu Y et al. Mol. Pharmacol. 59(3): 434, 2001) in amodified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 5 mM MgCl₂, 0.04% BSA)is used. Compounds of invention are incubated with 3 nM[³H]R(−)-α-Methylhistamine for 90 minutes at 25° C. Non-specific bindingis estimated in the presence of 1 μM R(−)-α-Methylhistamine. Receptorproteins are filtered and washed, the filters are counted to determine[³H]R(−)-α-Methylhistamine specifically bound. Compounds are screened at1 μM or lower, using 1% DMSO as vehicle. Compounds of the invention aretested in this biochemical assay and percent inhibition of specificbinding is determined.

Example B2 Determination of the Ability of Compounds of the Invention toBind a Imidazoline I₂ Receptor Central Imidazoline I₂

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat central imidazoline I₂ receptor obtained from WistarRat cerebral cortex (Brown, C. M. et al., Br. J. Pharmacol. 99:803,1990) in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5mM EDTA) was used. Compounds of the invention were incubated with 2 nM[³H]Idazoxan for 30 minutes at 25° C. Non-specific binding was estimatedin the presence of 1 μM Idazoxan. Receptor proteins were filtered andwashed, the filters were then counted to determine [³H]Idazoxanspecifically bound. Compounds were screened at 1 μM or lower, using 1%DMSO as vehicle. Compounds of the invention were tested in thisbiochemical assay and percent inhibition of specific binding wasdetermined. Certain compounds showed inhibition of specific binding byat least about 80%.

TABLE 3 Binding data (Percentage Inhibition) Histamine BindingImidazoline I₂ (1 μM) Example No. Compound No. Central (1 μM) H1 H2 19 140 77 5 20 2 18 95 71 21 3 20 83 51 23 5 35 36 32 14 0 12 33 15 0 −3 3416 16 1 35 17 54 −6 36 18 10 7 39 21 3 2 47 29 98 60 52 34 56 20 53 3598 67 56 38 33 16 3 58 40 7 4 61 43 30 6 62 44 62 9 94 52 3 −5 95 53 5 081 54 5 21 69 55 90 2 82 56 30 20 75 57 0 10 87 58 2 11 83 59 13 28 8460 19 15 85 61 49 17 86 62 48 48 78 66 19 1 79 67 35 8 71 70 39 1 70 7154 11 72 72 55 19 91 78 71 33 68 79 50 20 92 80 66 18 67 81 80 67 74 9029/48 64 80 91 28/42 68 66 92 99 50 110 97 20 89 111 98 40 94 112 99 6562 113 100 33 39 114 108 30 12 102 109 20 67 103 110 25 64 98 111 60 6197 112 33 38 115 113 26 81 96 114 30 75 105 115 50 71 104 116 8 50 99121 9 50 100 122 13 56 73 125 60 83 9 106 128 32 53 101 129 8 26 107 1305 51 108 132 14 57 109 155 2 49 124 159 5 20 125 160 31 67 126 161 51 82127 162 15 33 128 163 13 27 129 164 12 25 130 165 21 22 131 166 79 90132 167 64 51 133 168 85 64 134 169 20 50 135 170 27 60 136 171 15 17137 172 11 45 138 173 12 49 139 174 43 75 140 175 25 60 141 176 17 26142 177 11 39 143 178 44 54

Example B3 Determination of the Ability of Compounds of the Invention toBind an Adrenergic Receptor Adrenergic α_(1A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat adrenergic α_(1A) receptor obtained from Wistar Ratsubmaxillary glands (Michel, A. D. et al., Br. J. Pharmacol. 98:883,1989) in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5mM EDTA) is used. Compounds of the invention are incubated with 0.25 nM[³H]Prozosin for 60 minutes at 25° C. Non-specific binding is estimatedin the presence of 10 μM phentolamine. Receptor proteins are filteredand washed, the filters are then counted to determine [³H]Prozosinspecifically bound. Compounds of the invention are screened at 1 μM orlower, using 1% DMSO as vehicle. Compounds of the invention are testedin this biochemical assay and percent inhibition of specific binding isdetermined.

Adrenergic α_(1B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat adrenergic α_(1B) receptor obtained from Wistar Ratliver (Garcia-S'ainz, J. A. et al., Biochem. Biophys. Res. Commun.186:760, 1992; Michel A. D. et al., Br. J. Pharmacol. 98:883, 1989) in amodified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA) isused. Compounds of the invention are incubated with 0.25 nM [³H]Prozosinfor 60 minutes at 25° C. Non-specific binding is estimated in thepresence of 10 μM phentolamine. Receptor proteins are filtered andwashed, the filters are then counted to determine [³H]Prozosinspecifically bound. Compounds are screened at 1 μM or lower, using 1%DMSO as vehicle. Compounds of the invention are tested in thisbiochemical assay and percent inhibition of specific binding isdetermined.

Adrenergic α_(1D)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(1D) receptor expressed inhuman embryonic kidney (HEK-293) cells (Kenny, B. A. et al. Br. J.Pharmacol. 115(6):981, 1995) in a 50 mM Tris-HCl buffer, pH 7.4, wasused. Compounds of invention were incubated with 0.6 nM [³H]Prozosin for60 minutes at 25° C. Non-specific binding was estimated in the presenceof 10 μM phentolamine. Receptor proteins were filtered and washed, thefilters were then counted to determine [³H]Prozosin specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 4.

Adrenergic α_(2A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic (X²A receptor expressed ininsect Sf9 cells (Uhlen S et al. J Pharmacol Exp Ther. 271:1558, 1994)in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl₂, 2mM EDTA) was used. Compounds of invention were incubated with 1 nM[³H]MK-912 for 60 minutes at 25° C. MK912 is (2S-trans)-1,3,4,5′,6,6′,7,12b-octahydro-1′,3′-dimethyl-spiro[2H-benzofuro[2,3-a]quinolizine-2,4′(1′H)-pyrimidin]-2′(3′H)-onehydrochloride Non-specific binding was estimated in the presence of 10μM WB-4101 (2-(2,6-Dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxanehydrochloride). Receptor proteins were filtered and washed, the filterswere then counted to determine [³H]MK-912 specifically bound. Compoundswere screened at 1 μM or lower, using 1% DMSO as vehicle. Biochemicalassay results are presented as the percent inhibition of specificbinding in Table 4.

Adrenergic α_(2B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2B) receptor expressed inChinese hamster ovary (CHO-K1) cells (Uhlen S et al. Eur J. Pharmacol.343(1):93, 1998) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4,12.5 mM MgCl₂, 1 mM EDTA, 0.2% BSA) was used. Compounds of the inventionwere incubated with 2.5 nM [³H]Rauwolscine for 60 minutes at 25° C.Non-specific binding was estimated in the presence of 10 μM Prozosin.Receptor proteins were filtered and washed, the filters were thencounted to determine [³H]Rauwolscine specifically bound. Compounds werescreened at 1 μM or lower, using 1% DMSO as vehicle. Biochemical assayresults are presented as the percent inhibition of specific binding inTable 4.

Adrenergic α_(2c)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α2c receptor expressed ininsect Sf9 cells (Uhlen S et al. J Pharmacol Exp Ther. 271:1558, 1994)in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl₂, 2mM EDTA) is used. Compounds of the invention are incubated with 1 nM[³H]MK-912 for 60 minutes at 25° C. Non-specific binding is estimated inthe presence of 10 μM WB-4101. Receptor proteins are filtered andwashed, the filters are then counted to determine [³H]MK-912specifically bound. Compounds are screened at 1 μM or lower, using 1%DMSO as vehicle. Compounds of the invention are tested in thisbiochemical assay and percent inhibition of specific binding isdetermined.

Example B4 Determination of the Ability of Compounds of the Invention toBind a Dopamine Receptor Dopamine D_(2L)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant dopamine D2L receptor expressed inChinese hamster ovary (CHO) cells (Grandy, D. K. et al. Proc. Natl.Acad. Sci. USA. 86:9762, 1989; Hayes, G. et al., Mol. Endocrinol. 6:920,1992) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 1.4 mMAscorbic Acid, 0.001% BSA, 150 mM NaCl) was used. Compounds of theinvention were incubated with 0.16 nM [³H]Spiperone for 120 minutes at25° C. Non-specific binding was estimated in the presence of 10 μMHaloperidol. Receptor proteins were filtered and washed, the filterswere then counted to determine [³H]Spiperone specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 4.

TABLE 4 Percent Inhibition of ligand binding to aminergic Gprotein-coupled receptors by compounds of the invention: AdrenergicDopamine (1 μM Example Compound (1 μM ligand conc.) ligand conc.) No.No. α_(1D) α_(2A) α_(2B) D_(2L) 19 1 65 74 99 6 20 2 42 81 81 −7 21 3 7799 108 47 23 5 64 74 83 0 32 14 33 19 −16 6 33 15 5 15 8 −5 34 16 2 −4−7 −7 35 17 18 17 14 −3 36 18 21 4 19 0 39 21 −7 0 11 −1 47 29 84 96 7924 52 34 56 66 38 9 53 35 60 88 65 3 56 38 25 15 15 −8 58 40 3 1 18 −1161 43 58 42 −14 −8 62 44 61 77 20 8 94 52 −11 4 9 1 95 53 6 5 6 6 81 5411 4 18 −16 69 55 10 10 −21 −6 82 56 16 7 −10 9 75 57 77 4 29 6 87 58 19−12 −15 −5 83 59 30 91 97 35 84 60 29 79 −5 18 85 61 49 83 101 41 86 6244 90 102 81 78 66 74 55 74 9 79 67 85 85 106 21 71 70 44 81 77 0 70 7158 88 95 21 72 72 86 93 105 24 91 78 42 93 102 11 68 79 17 92 89 2 92 8089 82 100 5 67 81 64 92 102 21 74 90 62 88 97 36/39 80 91 73 95 94 27/4466 92 97 96 104 47 110 97 66 91 96 15 111 98 57 74 87 32 112 99 20 59 77−7 113 100 8 56 53 −11 114 108 −4 102 109 12 103 110 10 98 111 5 97 11212 115 113 9 96 114 8 105 115 0 104 116 0 99 121 21 100 122 21 73 125 9389 67 19 106 128 25 81 94 14 101 129 10 75 81 −8 107 130 −3 108 132 −813 84 −6 109 155 12 124 159 25 71 78 −9 125 160 25 51 75 −1 126 161 3252 92 0 127 162 19 76 85 4 128 163 78 96 37 −12 129 164 10 58 15 −2 130165 26 86 91 6 131 166 69 95 106 21 132 167 36 92 94 22 133 168 38 74 829 134 169 5 135 170 1 136 171 5 137 172 1 138 173 22 139 174 29 140 1750 141 176 −2 142 177 9 143 178 3

Example B5 Determination of the Ability of Compounds of the Invention toBind a Serotonin Receptor Serotonin (5-Hydroxytryptamine) 5-HT_(1A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT1Areceptor expressed in Chinese hamster ovary (CHO-K1) cells (Martin G Rand Humphrey P P A. Neuropharmacol. 33:261, 1994; May J A, et al. JPharmacol Exp Ther. 306(1): 301, 2003) in a modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 0.1% Ascorbic Acid, 0.5 mM EDTA, 10 mM MgSO₄) isused. Compounds of invention are incubated with 1.5 nM [³H]8-OH-DPAT for60 minutes at 25° C. Non-specific binding is estimated in the presenceof 10 μM Metergoline. Receptor proteins are filtered and washed, thefilters are then counted to determine [3H] 8-OH-DPAT specifically bound.Compounds are screened at 1 μM or lower, using 1% DMSO as vehicle.Compounds of the invention are tested in this biochemical assay andpercent inhibition of specific binding is determined.

Serotonin (5-Hydroxytryptamine) 5-HT1B

To evaluate in radioligand binding assays the activity of compounds ofthe invention, serotonin (5-Hydroxytryptamine) 5-HT1B receptor fromWistar Rat cerebral cortex (Hoyer et al. Eur J Pharmaco. 118: 1, 1985;Pazos et al. Eur J. Pharmacol. 106: 531, 1985) in a modified Tris-HClbuffer (50 mM Tris-HCl, pH 7.4, 154 mM NaCl, 10 μM Pargyline, 30 μMIsoprenaline) is used. Compounds of invention are incubated with 10 pM[¹²⁵I]Cyanopindolol for 90 minutes at 37° C. Non-specific binding isestimated in the presence of 10 μM Serotonin (5-HT). Receptor proteinsare filtered and washed, the filters are then counted to determine[¹²⁵]Cyanopindolol specifically bound. Compounds are screened at 1 μM orlower, using 1% DMSO as vehicle. Compounds of the invention are testedin this biochemical assay and percent inhibition of specific binding isdetermined.

Serotonin (5-Hydroxytryptamine) 5-HT_(2A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(2A) receptor expressed in Chinese hamster ovary (CHO-K1) cells(Bonhaus, D. W. et al. Br. J. Pharmacol. 115:622, 1995; Saucier, C. andAlbert, P. R., J. Neurochem. 68:1998, 1997) in a 50 mM Tris-HCl buffer,pH 7.4, was used. Compounds of the invention were incubated with 0.5 nM[³H]Ketanserin for 60 minutes at 25° C. Non-specific binding wasestimated in the presence of 1 μM Mianserin. Receptor proteins werefiltered and washed, the filters were then counted to determine [³H]Ketanserin specifically bound. Compounds were screened at 1 μM or lower,using 1% DMSO as vehicle. Biochemical assay results are presented as thepercent inhibition of specific binding in Table 5.

Serotonin (5-Hydroxytryptamine) 5-HT₂B

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT2Breceptor expressed in Chinese hamster ovary (CHO-K1) cells (Bonhaus, D.W. et al., Br. J. Pharmacol. 115:622, 1995) in a modified Tris-HClbuffer (50 mM Tris-HCl, pH 7.4, 4 mM CaCl₂, 0.1% Ascorbic Acid) is used.Compounds of invention are incubated with 1.2 nM [³H]Lysergic aciddiethylamide (LSD) for 60 minutes at 37° C. Non-specific binding isestimated in the presence of 10 μM Serotonin (5-HT). Receptor proteinsare filtered and washed, the filters are then counted to determine[³H]LSD specifically bound. Compounds are screened at 1 μM or lower,using 1% DMSO as vehicle. Compounds of the invention are tested in thisbiochemical assay and percent inhibition of specific binding isdetermined. Biochemical assay results may be presented as the percentinhibition of specific binding.

Serotonin (5-Hydroxytryptamine) 5-HT_(2c)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(2c) receptor expressed in Chinese hamster ovary (CHO-K1) cells(Wolf, W. A. and Schutz, J. S., J. Neurochem. 69:1449, 1997) in amodified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 0.1% Ascorbic Acid, 10μM Pargyline) was used. Compounds of the invention were incubated with 1nM [³H]Mesulergine for 60 minutes at 25° C. Non-specific binding wasestimated in the presence of 1 μM Mianserin. Receptor proteins werefiltered and washed, the filters were then counted to determine[³H]Mesulergine specifically bound. Compounds were screened at 1 μM orlower, using 1% DMSO as vehicle. Biochemical assay results are presentedas the percent inhibition of specific binding in Table 5.

Serotonin (5-Hydroxytryptamine) 5-HT₃

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₃receptor expressed in human embryonic kidney (HEK-293) cells (Miller Ket al. Synapase. 11:58, 1992; Boess F G et al. Neuropharmacology.36:637, 1997) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 1mM EDTA, 5 mM MgCl₂) is used. Compounds of invention are incubated with0.69 nM [³H]GR-65630 for 60 minutes at 25° C. Non-specific binding isestimated in the presence of 10 μM MDL-72222. Receptor proteins arefiltered and washed, the filters are then counted to determine[³H]GR-65630 specifically bound. Compounds are screened at 1 μM orlower, using 1% DMSO as vehicle. Compounds of the invention are testedin this biochemical assay and percent inhibition of specific binding isdetermined.

Serotonin (5-Hydroxytryptamine) 5-HT₄

To evaluate in radioligand binding assays the activity of compounds ofthe invention, serotonin (5-Hydroxytryptamine) 5-HT₄ receptor fromDuncan Hartley derived Guinea pig striatum (Grossman C J et al. Br J.Pharmacol. 109:618, 1993) in a 50 mM Tris-HCl, pH 7.4, is used.Compounds of invention are incubated with 0.7 nM [³H]GR-113808 for 30minutes at 25° C. Non-specific binding is estimated in the presence of30 μM Serotonin (5-HT). Receptor proteins are filtered and washed, thefilters are then counted to determine [³H] GR-113808 specifically bound.Compounds are screened at 1 μM or lower, using 1% DMSO as vehicle.Compounds of the invention are tested in this biochemical assay andpercent inhibition of specific binding is determined.

Serotonin (5-Hydroxytryptamine) 5-HT5A

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₅Areceptor expressed in Chinese hamster ovary (CHO-K1) cells (Rees, S. etal., FEBS Lett. 355:242, 1994) in a modified Tris-HCl buffer (50 mMTris-HCl, pH 7.4, 10 mM MgCl₂, 0.5 mM EDTA) was used. Compounds of theinvention were incubated with 1.7 nM [³H]Lysergic acid diethylamide(LSD) for 60 minutes at 37° C. Non-specific binding was estimated in thepresence of 100 μM Serotonin (5-HT). Receptor proteins were filtered andwashed, the filters were then counted to determine [³H]LSD specificallybound. Compounds were screened at 1 μM or lower, using 1% DMSO asvehicle. Compounds of the invention were tested in this biochemicalassay and percent inhibition of specific binding was determined.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 5.

Serotonin (5-Hydroxytryptamine) 5-HT₆

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT6receptor expressed in human HeLa cells (Monsma, F. J. Jr. et al., Mol.Pharmacol. 43:320, 1993) in a modified Tris-HCl buffer (50 mM Tris-HCl,pH 7.4, 150 mM NaCl, 2 mM Ascorbic Acid, 0.001% BSA) was used. Compoundsof the invention were incubated with 1.5 nM [3H]Lysergic aciddiethylamide (LSD) for 120 minutes at 37° C. Non-specific binding wasestimated in the presence of 5 μM Serotonin (5-HT). Receptor proteinswere filtered and washed, the filters were then counted to determine[3H]LSD specifically bound. Compounds were screened at 1 μM or lower,using 1% DMSO as vehicle. Biochemical assay results are presented as thepercent inhibition of specific binding in Table 5.

Serotonin (5-Hydroxytryptamine) 5-HT₇

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₇receptor expressed in Chinese hamster ovary (CHO) cells (Roth, B. L. etal., J. Pharmacol. Exp. Ther. 268:1403, 1994; Shen, Y. et al., J. Biol.Chem. 268:18200, 1993) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH7.4, 10 mM MgCl₂, 0.5 mM EDTA) was used. Compounds of invention wereincubated with 5.5 nM [³H] Lysergic acid diethylamide (LSD) for 2 hoursat 25° C. Non-specific binding was estimated in the presence of 10 μMSerotonin (5-HT). Receptor proteins were filtered and washed, thefilters were then counted to determine [³H]LSD specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 5.

TABLE 5 Percent Inhibition of ligand binding to aminergic Gprotein-coupled receptors by compounds of the invention: SerotoninExample Compound (1 μM ligand concentration) No. No. 5-HT_(2A) 5-HT_(2C)5-HT₆ 5-HT₇ 19 1 25 5 20 2 84 58 21 3 90 100 23 5 51 39 6 32 14 27 20 1233 15 6 15 −2 34 16 10 −18 9 35 17 17 3 3 36 18 −1 3 1 39 21 4 16 6 4729 83 90 62 52 34 31 37 16 53 35 69 87 67 56 38 14 −2 58 40 5 12 6 61 4369 31 3 62 44 73 54 12 94 52 −11 −4 −4 95 53 −6 −3 −8 81 54 0 −1 8 69 5517 13 0 82 56 12 −3 −3 75 57 28 14 6 87 58 −10 30 −7 83 59 80 74 60 8460 74 5 62 85 61 86 81 61 86 62 88 95 77 78 66 51 48 5 79 67 77 85 51 7170 56 63 21 70 71 87 81 66 72 72 96 89 61 91 78 80 101 48 99 68 79 62 7727 85 92 80 56 79 23 82 67 81 93 88 96 82 74 90 97 99 98 80 91 97 104100 66 92 97 96 96 110 97 97 99 72 98 111 98 98 103 79 94 112 99 86 9769 68 113 100 87 98 23 42 114 108 45 60 6 62 102 109 96 97 72 96 103 11093 97 73 87 98 111 79 93 88 78 97 112 82 94 61 67 115 113 99 91 49 84 96114 93 95 42 87 105 115 85 86 40 74 104 116 83 85 38 51 99 121 96 102 3394 100 122 95 102 36 95 73 125 74 66 106 128 95 101 90 24 101 129 85 10722 15 107 130 91 95 7 22 108 132 80 94 17 35 109 155 85 95 14 19 124 15989 103 46 49 125 160 95 103 24 84 126 161 96 99 75 93 127 162 98 101 1227 128 163 98 96 89 29 129 164 95 98 16 8 130 165 85 93 46 91 131 166102 96 95 92 132 167 88 95 55 97 133 168 94 96 71 84 134 169 80 91 24 78135 170 96 98 36 74 136 171 80 92 36 13 137 172 96 100 10 1 138 173 9590 48 81 139 174 98 89 33 74 140 175 86 97 77 82 141 176 81 94 26 53 142177 83 88 6 57 143 178 97 101 25 59

Example B6 Determination of Serotonin (5-Hydroxytryptamine) 5-HT_(2A)Agonist/Antagonist Activity of Compounds of the Invention

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant serotonin 5-HT_(2A)receptor expressed in human embryonic kidney (HEK-293) cells (Jerman JC, Brough S J, Gager T, Wood M, Coldwell M C, Smart D and Middlemiss DN. Eur J Pharmacol, 414: 23-30, 2001) is used. Cells are suspended inDMEM buffer, and distributed in microplates. A cytoplasmic calciumfluorescent indicator which varies proportionally to the free cytosolicCa²⁺ ion concentration is mixed with probenicid in HBSS buffercomplemented with 20 mM Hepes (pH 7.4), added into each well andequilibrated with the cells for 30 min at 37° C. followed by 30 min at22° C.

To measure agonist effects, compounds of the invention, referenceagonist or HBSS buffer (basal control) is added to the cells and changesin fluorescence intensity are measured using a microplate reader. Forstimulated control measurements, 5-HT at 100 nM is added in separateassay wells.

The results are expressed as a percent of the control response to 100 nM5-HT. The standard reference agonist is 5-HT, which is tested in eachexperiment at several concentrations to generate aconcentration-response curve from which its EC₅₀ value is calculated.

To measure antagonist effects, the addition of the compounds of theinvention, reference antagonist or HBSS buffer is followed by theaddition of 3 nM 5-HT or HBSS buffer (basal control) prior thefluorescence measurements. The results are expressed as a percentinhibition of the control response to 3 nM 5-HT. The standard referenceantagonist is ketanserin, which is tested in each experiment at severalconcentrations to generate a concentration-response curve from which itsIC₅₀ value is calculated. Compounds are screened at 3 μM or lower, usingDMSO as vehicle.

Example B7 Determination of Serotonin (5-Hydroxytryptamine) 5-HT₆Agonist/Antagonist Activity of Compounds of the Invention

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant 5-HT₆ receptor istransfected in CHO cells (Kohen, R., Metcalf, M. A., Khan, N., Druck,T., Huebner, K., Lachowicz, J. E., Meltzer, H. Y., Sibley, D. R., Roth,B. L. And Hamblin, M. W. Cloning, characterisation and chromosomallocalization of a human 5-HT6 serotonin receptor, J. Neurochem., 66: 47,1996) and the activity of compounds of the invention is determined bymeasuring their effects on cAMP production using the Homogeneous TimeResolved Fluorescence (HTRF) detection method. Cells are suspended inHBSS buffer complemented with HEPES 20 mM (pH 7.4) and 500 μM IBMX, andthen distributed in microplates and incubated for 45 min at 37° C. inthe absence (control) or presence of compounds of the invention or thereference agonist or antagonist.

For agonist determinations, stimulated control measurement, separateassay wells contain 10 μM 5-HT. Following incubation, the cells arelysed and the fluorescence acceptor (D2-labeled cAMP) and fluorescencedonor (anti-cAMP antibody labeled with europium cryptate) are added.After 60 min at room temperature, the fluorescence transfer is measuredat lex=337 nm and lem=620 and 665 nm using a microplate reader. The cAMPconcentration is determined by dividing the signal measured at 665 nm bythat measured at 620 nm (ratio).

The results are expressed as a percent of the control response to 10 μM5-HT. The standard reference agonist is 5-HT, which is tested in eachexperiment at several concentrations to generate aconcentration-response curve from which its EC₅₀ value is calculated.

For antagonist determinations, the reference agonist 5-HT is added at afinal concentration of 100 nM. For basal control measurements, separateassay wells do not contain 5-HT. Following 45 min incubation at 37° C.,the cells are lysed and the fluorescence acceptor (D2-labeled cAMP) andfluorescence donor (anti-cAMP antibody labeled with europium cryptate)are added.

After 60 min at room temperature, the fluorescence transfer is measuredas mentioned above. The results are expressed as a percent inhibition ofthe control response to 100 nM 5-HT. The standard reference antagonistis methiothepin

Example B8 Determination of Dopamine D₂₁ Antagonist Activity ofCompounds

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant dopamine D2L receptorstably expressed in Chinese hamster ovary (CHO) cells (Senogles S E etal. J Biol. Chem. 265(8): 4507, 1990) is used. Compounds of inventionare pre-incubated with the membranes (0.1 mg/ml) and 10 mM GDP inmodified HEPES buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl₂, 1mM DTT, 1 mM EDTA) for 20 minutes and Scintillation Proximity Assay(SPA) beads are added for another 60 minutes at 30° C. The reaction isinitiated by 0.3 nM [³⁵S]GTPγS for an additional 15 minute incubationperiod. Increase of [³⁵S]GTPγS binding by 50 percent or more (350%)relative to the 1 mM dopamine response by compounds of the inventionindicates possible dopamine D2L receptor agonists activity. Inhibitionof a 10 μM dopamine-induced increase of [³⁵S]GTPγS binding response by50 percent or more (350%) by compounds of the invention indicatesreceptor antagonist activity. Compounds are screened at 3 μM or lower,using 0.4% DMSO as vehicle. Assay results are presented as the percentresponse of specific binding.

Example B9 Determination of Dopamine D_(2S) Antagonist Activity ofCompounds of the Invention

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant dopamine D2s receptorstably expressed in Chinese hamster ovary (CHO) cells (Gilliland S L andAlper R H. Naunyn-Schmiedeberg's Archives of Pharmacology. 361: 498,2000) is used. Compounds of invention are pre-incubated with themembranes (0.05 mg/ml) and 3 μM GDP in modified HEPES buffer (20 mMHEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl₂, 1 mM DTT, 1 mM EDTA) for 20minutes and Scintillation Proximity Assay (SPA) beads are then added foranother 60 minutes at 30° C. The reaction is initiated by 0.3 nM[³⁵S]GTPγS for an additional 30 minute incubation period. Increase of[³⁵S]GTPγS binding by 50 percent or more (350%) relative to the 100 μMdopamine response by compounds of the invention indicates possibledopamine D2s receptor agonists activity. Inhibition of a 3 μMdopamine-induced increase of [³⁵S]GTPγS binding response by 50 percentor more (350%) by compounds of the invention indicates receptorantagonist activity. Compounds are screened at 3 μM or lower, using 0.4%DMSO as vehicle. Assay results are presented as the percent response ofspecific binding.

Example B10 Determination for Agonist or Antagonist Activity ofCompounds of the Invention in a Histamine H1 Functional Assay

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant Histamine H1 receptorexpressed in human embryonic kidney (HEK-293) cells (Miller, T. R.,Witte, D. G., Ireland, L. M., Kang, C. H., Roch, J. M., Masters, J. N.,Esbenshade, T. A And Hancock, A. A. J. Biomol. Screen., 4: 249-258,1999) is used. Cells are suspended in DMEM buffer, and then distributedin microplates. A cytoplasmic calcium fluorescent indicator-which variesproportionally to the free cytosolic Ca²⁺ ion concentration—is mixedwith probenicid in HBSS buffer complemented with 20 mM Hepes (pH 7.4)and is then added into each well and equilibrated with the cells for 30min at 37° C. and then for another 30 min at 22° C. To measure agonisteffects, compounds of the invention, reference agonist or HBSS buffer(basal control) are added to the cells and changes in fluorescenceintensity are measured using a microplate reader. For stimulated controlmeasurements, histamine at 10 μM is added in separate assay wells.

The results are expressed as a percent of the control response to 10 μMhistamine. The standard reference agonist is histamine, which is testedin each experiment at several concentrations to generate aconcentration-response curve from which its EC₅₀ value is calculated.

To measure antagonist effects, the addition of the compounds of theinvention, reference antagonist or HBSS buffer is followed by theaddition of 300 nM histamine or HBSS buffer (basal control) prior thefluorescence measurements. The results are expressed as percentinhibition of the control response to 300 nM histamine. The standardreference antagonist is ketanserin, which is tested in each experimentat several concentrations to generate a concentration-response curvefrom which its IC₅₀ value is calculated. Compounds are screened at 3 μMor lower, using DMSO as vehicle.

Example B11 Increase of Neurite Outgrowth Neurite Outgrowth in CorticalNeurons

Compounds are tested to determine their ability to stimulate neuriteoutgrowth of cortical neurons. Standard methods are used to isolatecortical neurons. For the isolation of primary rat cortical neurons, thefetal brain from a pregnant rat at 17 days of gestation was prepared inLeibovitz's medium (L15; Gibco). The cortex is dissected out, and themeninges were removed. Trypsin (Gibco) is used to dissociate cortical Cwith DNAse I. The cells are triturated for 30 minutes with a pipette inDulbecco's Modified Eagle Media (“DMEM”; Gibco) with 10% Fetal BovineSerum (“FBS”) (Gibco) and centrifuged at 350×g for 10 minutes at roomtemperature. The cells are suspended in Neurobasal medium supplementedwith 2% B27 (Gibco) and 0.5 mM L-glutamine (Gibco). The cells aremaintained at 30,000 cells per well of poly-L-lysine coated plates at37° C. in 5% CO₂-95% air atmosphere. After adhesion, a vehicle controlor compounds of the invention are added at different concentrations tothe medium. BDNF (50 ng/mL) is used as a positive control for neuritegrowth. After treatment, cultures are washed in phosphate-bufferedsaline (“PBS”; Gibco) and fixed in glutaraldehyde 2.5% in PBS. Cells arefixed after 3 days growth. Several pictures (˜80) of cells with neuritesare taken per condition with a camera. The length measurements are madeby analysis of the pictures using software from Image-Pro Plus (France).The results are expressed as mean (s.e.m.). Statistical analysis of thedata is performed using one way analysis of variance (ANOVA).

Neurite Outgrowth in Rat Mixed Cortical Cultures

Cortical mixed cultures are prepared from E18 Wistar rat embryos. Thecortices are dissected out and the tissue was cut to small pieces. Thecells are separated by 15-min incubation with DNase and papain. Thecells are collected by centrifugation (1500 rpm, 5 min). The tissue istriturated with a pipette and the cells are plated using the micro-isletprotocol (20 000 cells in 25 μl medium) on poly-L-lysine coated 48wells, in MEM supplemented with 2 mM glutamine, 0.1 μg/ml gentamicin,10% heat-inactivated fetal bovine serum (FBS-HI) and 10%heat-inactivated horse serum (HS-HI). After the cells attach to thewell, 250 μl medium is added to the wells. Four hours after plating themedium is changed to fresh medium (MEM with supplements and 5% HS-HI)containing test compound at 0.5, 5 and 50 nM concentrations. As positivecontrols BDNF (50, 100 and/or 150 ng/ml), and/or NGF (50 ng/ml and/or100 ng/ml) are used. After 2 days in vitro, the cell's conditioned mediaare collected from plates before fixing the cells. The media samples arecentrifuged 13 000 rpm 3 min to get rid of cell debris. The samples arestored at −20° C. for later analysis. Cells are formaldehyde-fixed andprocessed for immunocytochemistry. BDNF levels in the conditioned mediaare determined with a BDNF ELISA using the manufacturers (Promega, BDNFEmax® ImmunoAssay System, catalog number: G7610) instructions.

The cultures are fixed with 4% formaldehyde in 0.01 M PBS for 30 min andwashed once with PBS. The fixed cells are first permeabilized andnon-specific binding is blocked by a 30-min incubation with blockingbuffer containing 1% bovine serum albumin and 0.3% Triton X-100 in PBS.Rabbit anti-MAP-2 (dilution 1:1000, AB5622, Chemicon, in blockingbuffer) is used as a primary antibody. The cells are incubated with theprimary antibody for 48 h at +4° C., washed with PBS and incubated withsecondary antibody goat anti-rabbit IgG conjugated to Alexa Fluor568(1:200, A11036, Molecular Probes) for 2 h at RT. The immunopositivecells are visualized by a fluorescence microscope equipped withappropriate filter set, and documented by a high resolution imagecapturing. The number of cells per field (4 field per well) are counted,and the neurite outgrowth is quantified using Image Pro Plus software.

The number of wells per compound concentration used is 6 (n=6). All dataare presented as mean±standard deviation (SD) or standard error of mean(SEM), and differences are considered to be statistically significant atthe p<0.05 level. Statistical analysis is performed using StatsDirectstatistical software. Differences between group means are analyzed byusing 1-way-ANOVA followed by Dunnet's test (comparison to the vehicletreated group).

Example B12 Use of an In Vivo Model to Evaluate the Ability of Compoundsto Enhance Cognition, Learning and Memory in Scopolamine Treated Rats

The two-trial object recognition paradigm developed by Ennaceur andDelacour in the rat is used as a model of episodic/short-term memory.Ennaceur, A., and Delacour, J. (1988), Behav. Brain Res. 31:47-59. Theparadigm is based on spontaneous exploratory activity of rodents anddoes not involve rule learning or reinforcement. The novel objectrecognition paradigm is sensitive to the effects of ageing andcholinergic dysfunction. See, e.g., Scali, C., et al., (1994), Neurosci.Letts. 170:117-120; and Bartolini, L., et al., (1996), Biochem. Behav.53:277-283.

Male Sprague-Dawley rats between six and seven weeks old, weighingbetween 220-300 grams are obtained, e.g., from Centre d'Elevage (RueJanvier, B. P. 55, Le Genest-Saint-Isle 53940, France). The animals arehoused in groups of 2 to 4 in polypropylene cages (with a floor area of1032 cm²) under standard conditions: at room temperature (22±2° C.),under a 12 hour light/12 hour dark cycle, with food and water providedad libitum. Animals are permitted to acclimate to environmentalconditions for at least 5 days before the experiment begins, and arenumbered on their tails with indelible marker.

The experimental arena is a square wooden box (60 cm×60 cm×40 cm)painted dark blue, with 15 cm×15 cm black squares under a clearplexiglass floor. The arena and objects placed inside the arena arecleaned with water between each trial to eliminate any odor trails leftby rats. The arena is placed in a dark room illuminated only by halogenlamps directed towards the ceiling in order to produce a uniformly dimlight in the box of approximately 60 lux. The day before testing,animals are allowed to freely explore the experimental arena for threeminutes in the presence of two objects (habituation). Animals to betested are placed in the experimental room at least 30 minutes beforetesting.

Novel object recognition test is comprised of two trials separated by aninterval of 120 minutes or 24 hours. When agents that disrupt memorysuch as the cholinergic antagonist scopolamine are used an inter-trialinterval of 120 minutes is preferred. Alternatively a 24 hoursinter-trial interval is used when studying effect of natural forgettingon novel object recognition task. During the first, or acquisition,trial (T₁), rats are placed in the arena, where two identical objectshave been previously placed. The time required for each animal tocomplete 15 seconds of object exploration is determined, with a cut-offtime of four minutes. Exploration is considered to be directing the noseat a distance less than 2 centimeters (“cm”) from the object and/ortouching the object. During the second, or testing, trial (T₂), one ofthe objects presented in the first trial is replaced with an unknown ornovel object, while the second, familiar object is left in place. Ratsare placed back in the arena for three minutes, and exploration of bothobjects is determined. Locomotor activity of rats (number of times ratscross grid lines visible under the clear plexiglass floor) is scored forduring T₁ and T₂. At the conclusion of the experiments, the rats aresacrificed by an overdose of pentobarbital given intraperitoneally.

The following parameters are measured as part of the novel objectrecognition task: (1) time required to achieve 15 seconds of objectexploration during T₁; (2) locomotor activity during T₁ (number ofcrossed lines); (3) time spent in active exploration of the familiarobject during T₂ (T_(Familiar)); (4) time spent in active exploration ofthe novel object during T₂ (T_(Novel)); and (5) locomotor activityduring T₂ (number of crossed lines). The difference between time spentin active exploration of the novel object during T₂ and time spent inactive exploration of the familiar object during T₂ (ΔT_(Novel)-T_(Familiar)) is evaluated. The % of animals in each groupwith T_(Novel)-T_(Familiar) greater than or equal to 5 seconds is alsoderived; described as % of good learners.

Animals not meeting a minimal level of object exploration are excludedfrom the study as having naturally low levels of spontaneousexploration. Thus, only rats exploring the objects for at least fiveseconds (T_(Novel)+T_(Familiar)>5 seconds) are included in the study.

Animals are randomly assigned to groups of 14. Compounds of theinvention and controls are administered to animals the groups asfollows: Solutions of compounds are prepared freshly each day at aconcentration of 0.25 mg/ml using purified water or saline as vehicle.Donepezil, used as a positive control, and scopolamine are administeredsimultaneously in a single solution of saline (5 mL/kg) prepared freshlyeach day. Scopolamine is purchased from Sigma Chemical Co. (Catalog No.S-1875; St. Quentin Fallavier, France) is dissolved in saline to aconcentration of 0.06 mg/mL.

Donepezil or its vehicle and scopolamine are administeredintraperitoneally forty minutes before the acquisition trial (T₁).Compounds or their vehicle are administered by gavage twenty-fiveminutes before the acquisition trial (T₁), i.e., five minutes afteradministration of scopolamine. The volume of administration is 5 ml/kgbody weight for compounds administered intraperitoneally, and 10 ml/kgfor compounds administered orally. Recognition scores and % of goodlearners for compounds are determined.

Example B13 Use of an In Vivo Model to Determine the Ability ofCompounds to Treat, Prevent and/or Delay the Onset and/or theDevelopment of Schizophrenia in PCP Treated Animals

In vivo models of schizophrenia can be used to determine the ability ofthe compounds described herein to treat and/or prevent and/or delay theonset and/or the development of schizophrenia.

One exemplary model for testing the activity of one or more compoundsdescribed herein to treat and/or prevent and/or delay the onset and/ordevelopment of schizophrenia employs phencyclidine (PCP), which isadministered to the animal (e.g., non-primate (rat) or primate(monkey)), resulting in dysfunctions similar to those seen inschizophrenic humans. See Jentsch et al., 1997, Science 277:953-955 andPiercey et al., 1988, Life Sci. 43(4):375-385). Standard experimentalprotocols may be employed in this or in other animal models. Oneprotocol involves PCP-induced hyperactivity.

Male mice (various strains, e.g., C57B1/6J) from appropriate vendor (forexample, Jackson Laboratories (Bar Harbor, Me.) are used. Mice arereceived at 6-weeks of age. Upon receipt, mice are assigned uniqueidentification numbers (tail marked) and are group housed with 4mice/cage in OPTI mouse ventilated cages. All animals remain housed ingroups of four during the remainder of the study. All mice areacclimated to the colony room for at least two weeks prior to testingand are subsequently tested at an average age of 8 weeks. During theperiod of acclimation, mice are examined on a regular basis, handled,and weighed to assure adequate health and suitability. Animals aremaintained on a 12/12 light/dark cycle. The room temperature ismaintained between 20 and 23° C. with a relative humidity maintainedbetween 30% and 70%. Food and water are provided ad libitum for theduration of the study. In each test, animals are randomly assignedacross treatment groups.

The open filed (OF) test assesses locomotor behavior, i.e. to measuremouse locomotor activity at baseline and in response to pharmacologicalagents. The open field chambers are Plexiglas square chambers(27.3×27.3×20.3 cm; Med Associates Inc., St Albans, Vt.) surrounded byinfrared photobeams (16×16×16) to measure horizontal and verticalactivity. The analysis is configured to divide the open field into acenter and periphery zone such that the infrared photobeams allowmeasurement of activity in the center and periphery of the field.Distance traveled is measured from horizontal beam breaks as the mousemoved whereas rearing activity is measured from vertical beam breaks.

Mice (10 to 12 animals per treatment group) are brought to the activityexperimental room for at least 1 hr acclimation to the experimental roomconditions prior to testing. Eight animals are tested in each run. Miceare administered vehicle (e.g. 10% DMSO or 5% PEG200 and 1% Tween 80),compound of the invention, clozapine (positive control, 1 mg/kg ip) andplaced in the OF chambers for 30 min following which they are injectedwith either water or PCP and placed back in the OF chambers for a60-minute session. At the end of each OF test session the OF chambersare thoroughly cleaned.

PCP Hyperactivity Mouse Model of Schizophrenia

The test compound at the desired dose is dissolved in appropriatevehicle, e.g., 5% PEG200, 1% Tween80 and administered orally 30 minprior to PCP injection. Clozapine (1 mg/kg) is dissolved in 10% DMSO andadministered i.p. 30 min prior to PCP injection. PCP (5 mg/kg) isdissolved in sterile injectable saline solution and administered i.p.

Data are analyzed by analysis of variance (ANOVA) followed by post-hoccomparisons with Fisher Tests when appropriate. Baseline activity ismeasured during the first 30 min of the test prior to PCP injection.PCP-induced activity is measured during the 60 min following PCPinjection. Statistical outliers that fell above or below 2 standarddeviations from the mean are removed from the final analyses. An effectis considered significant if p<0.05. Total distances traveled and totalrearing following PCP administration are compared between groups treatedwith compounds and groups treated with vehicle and positive controlclozapine.

PCP Hyperactivity Mouse Model of Schizophrenia

Protocol is as described above with the exception of the treatmentgroups which are as follows: All injections are at a dose volume of 10ml/kg. The test compound at the desired dose is dissolved in PhosphateBuffered Saline (PBS) and administered orally 30 min prior to PCPinjection. Clozapine (0.5 and 1.0 mg/kg) is dissolved in 10% DMSO andadministered i.p. 30 min prior to Phencyclidine (PCP) injection. PCP(5.0 mg/kg) is dissolved in sterile injectable saline and administeredi.p. Total distances traveled for is determined.

Example B14 Use of an In Vivo Model to Determine the Ability ofCompounds to Treat, Prevent and/or Delay the Onset and/or theDevelopment of Schizophrenia in Amphetamine Treated Animals

Male mice (various strains e.g., C57B1/6J) from appropriate supplier(for example Jackson Laboratories, Bar Harbor, Me.) are used. Micetypically are received at 6-weeks of age. Mice are acclimated to thecolony room for at least two weeks prior to testing. During the periodof acclimation, mice are examined on a regular basis, handled, andweighed to assure adequate health and suitability and maintained on a12/12 light/dark cycle. The room temperature is maintained between 20and 23° C. with a relative humidity maintained between 30% and 70%. Foodand water are provided ad libitum for the duration of the study. In eachtest, animals are randomly assigned between treatment groups.

The open field test (OF) is used to assess motor activity. The openfield chambers are plexiglass square chambers (e.g., 27.3×27.3×20.3 cm;Med Associates Inc., St Albans, Vt.) surrounded by infrared photobeamsources (16×16×16). The enclosure is configured to split the open fieldinto a center and periphery zone and the photocell beams are set tomeasure activity in the center and in the periphery of the OF chambers.Horizontal activity (distance traveled) and vertical activity (rearing)are measured from consecutive beam breaks.

On the day of testing, animals are brought to the experimental room forat least 1 hr acclimation prior to start of treatment. Animals areadministered with vehicle, haloperidol (positive control, 0.1 mg/kg ip)or test compound and placed in the OF. The time of administration ofclient compound to each animal is recorded. Baseline activity isrecorded for 30 min following which mice receive amphetamine (4 mg/kg)or water and are placed back in the OF chambers for a 60-minute session.At the end of each open field test session the OF chambers arethoroughly cleaned. Typically ten to twelve mice are tested in eachgroup. Test compound doses typically range from 0.01 mg/kg to 60 mg/kg.

Data are analyzed by analysis of variance (ANOVA) followed by post-hoccomparisons with Fisher Tests when appropriate. Baseline activity ismeasured during the first 30 min of the test prior to amphetamineinjection. Amphetamine-induced activity is measured during the 60 minfollowing amphetamine injection. Statistical outliers that fall above orbelow 2 standard deviations from the mean are removed from the finalanalyses. An effect is considered significant if p<0.05. Total distancetraveled and total rearing following amphetamine administration arecompared between groups treated with compound and groups treated withvehicle and positive control haloperidol.

Example B15 Use of the In Vivo Conditioned Avoidance Response (Car)Model to Determine the Ability of Compounds to Treat, Prevent and/orDelay the Onset and/or the Development of Schizophrenia

All currently approved antipsychotic agents (typical and atypical) areknown to have the ability to selectively suppress conditioned avoidanceresponse (CAR) behavior in the rat. This evidence makes CAR one of theprimary tests to assess antipsychotic activity of novel compounds.

Rats (various strains, 2 months of age) are trained and tested in acomputer-assisted, two-way active avoidance apparatus (shuttle box).This box consists of two compartments of equal size divided by astainless steel partition containing an opening of 7×7 cm. Eachcompartment is equipped with an electrified grid floor made of stainlesssteel rods spaced 1 cm apart. Rats trained to avoid the foot shock areplaced each day in the shuttle box for a 4 minutes habituation periodfollowed by 30 trials spaced by inter-trial interval varying at randombetween 20 and 30 seconds. Each trial consists of a 10-second stimuluslight (conditioned stimulus, CS) followed by a 10-second foot shock(unconditioned stimulus, US) in presence of the light presented in thecompartment where the rat is located. If the animal leaves thecompartment prior to the delivery of the foot shock, the response isconsidered an avoidance response. If the rat does not change compartmentduring the 10-second light period and during the 10-second shock+lightperiod, an escape failure is recorded. This test requires animals to betrained 5 days/week. On each training day, rats are submitted to onetraining session of 30-trials. Treatment with test compound is initiatedonly when rats reach an avoidance performance of at least 80% on atleast two consecutive training sessions. The test compound isadministered orally at various doses and various pre-treatment times(depending upon specific pharmacokinetic properties).

Compounds with antipsychotic profile inhibit conditioned avoidanceresponses with or without increases in escape failures. Statisticalanalysis is performed using a Friedman two-way ANOVA by ranks followedby the Wilcoxon matched-pairs signed-ranks test to test each dose of thetest compound administered versus vehicle control treated rats.

The ability of compounds of the invention to bind receptors detailedhereinabove is evaluated in multiple concentrations. Examples of assayresults are shown in Table 6.

TABLE 6 Percentage inhibition of ligand binding to receptors bycompounds of the invention: Com- Com- Com- Com- Compound pound poundpound pound Receptor Concentration No. 90 No. 91 No. 92 No. 166Adrenergic α_(1D) 1 μM 62 73 97 69 Adrenergic α_(2A) 1 μM 88 95 96 95Adrenergic α_(2B) 1 μM 97 94 104 106 D_(2L) 10 μM 91 91 50 1 μM 39 44 4721 3 μM 70 64 72 12 H1 0.03 μM 67 0.1 μM 91 0.3 μM 96 23 10 μM 94 95 1μM 48 42 99 79 3 μM 76 75 77 H2 1 μM 64 68 50 90 5-HT_(2A) 0.03 μM 31 5437 46 0.1 μM 64 79 65 74 0.3 μM 87 92 83 81 10 nM 9 21 13 15 1 μM 97 9797 102 3 nM 1 2 5-HT_(2C) 0.03 μM 65 77 62 0.1 μM 82 87 87 0.3 μM 93 9393 10 nM 37 58 33 1 μM 99 104 96 96 3 nM 22 22 5-HT₆ 0.03 μM 58 68 28 160.1 μM 81 84 60 38 0.3 μM 94 96 81 55 10 nM 32 42 14 13 1 μM 98 100 9695 3 nM 16 15 5-HT₇ 0.03 μM 29 53 0.1 μM 63 83 0.3 μM 86 87 10 nM 15 361 μM 92 3 nM −2 19

All references throughout, such as publications, patents, patentapplications and published patent applications, are incorporated hereinby reference in their entireties.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

1. A compound of the formula (F):

wherein: R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thioalkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(2a) and R^(2b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano,hydroxyl, alkoxy or nitro, or R^(2a) and R^(2b) are taken together withthe carbon to which they are attached to form a cycloalkyl moiety or acarbonyl moiety; each R^(3a) and R^(3b) is independently H, substitutedor unsubstituted C₁-C₈ alkyl, halo, cyano, nitro, hydroxyl, alkoxy,amino, substituted amino, cycloalkyl, phenyl, acylamino or acyloxy, orR^(3a) and R^(3b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety or a carbonyl moiety; each X⁷, X⁸,X⁹ and X¹⁰ is independently N or CR⁴; m and q are independently 0 or 1;each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl; each R^(8a), R^(8b), R^(8c) and R^(8d) isindependently H, hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy,carbonylalkoxy, is taken together with the carbon to which it isattached and a geminal R^(8(a-d)) to form a cycloalkyl moiety or acarbonyl moiety, or is taken together with a geminal R^(8(a-d)) to forma methylene or a substituted methylene; each R^(10a) and R^(10a) isindependently H, halo, a substituted or unsubstituted C₁-C₈ alkyl,hydroxyl, alkoxyl, cyano or nitro, or R^(1a) and R^(10b) are takentogether with the carbon to which they are attached to form a cycloalkylmoiety or a carbonyl moiety; R¹¹ and R¹² are independently H or C₁-C₈alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, or are takentogether with the carbon atoms to which they are attached to form asubstituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl or substituted or unsubstitutedheterocyclyl moiety or are taken together to form a bond, therebyproviding an acetylenyl moiety;

indicates the presence of either an E or Z double bond configurationwhen R¹¹ and R¹² are independently H, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl,carboxy or carbonylalkoxy; and Q is a substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or aunsubstituted heterocyclyl, unsubstituted amino, substituted amino,alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy,acylamino, carboxy, cyano or alkynyl; or a pharmaceutically acceptablesalt thereof.
 2. The compound of claim 1 or a pharmaceuticallyacceptable salt thereof, wherein R¹ is unsubstituted C₁-C₈ alkyl.
 3. Thecompound of claim 2, or a pharmaceutically acceptable salt thereof,wherein Q is phenyl or substituted phenyl.
 4. The compound according toclaim 1, wherein any one or more of (i)-(xi) apply, provided thatprovisions (iv) and (v) are not combined, provisions (ii) and (xi) arenot combined and (iii) and (xi) are not combined: (i) q and m are both0; (ii) R¹¹ is H; (iii) R¹² is an unsubstituted C₁-C₈ alkyl; (iv) one ofR^(3a) and R^(3b) is methyl, ethyl or phenyl and the other is H; (v)R^(3a) and R^(3b) are both H; (vi) R¹ is an unsubstituted C₁-C₈ alkyl;(vii) X⁹ is CR⁴ where R⁴ is unsubstituted C₁-C₈ alkyl or halo; (viii)X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ is H; (ix) R^(2a) and R^(2b) areboth H; (x) R^(10a) and R^(10b) are both H; and (xi) R¹¹ and R¹² aretaken together to form a bond.
 5. A compound of the formula (E-2):

wherein: each R^(2a) and R^(2b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy or nitro, orR^(2a) and R^(2b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety or a carbonyl moiety; each R^(3a)and R^(3b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, nitro, hydroxyl, alkoxy, amino, substituted amino,cycloalkyl, acylamino or acyloxy or R^(3a) and R^(3b) are taken togetherwith the carbon to which they are attached to form a cycloalkyl moietyor a carbonyl moiety; each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;q is independently 0 or 1; each R⁴ is independently H, hydroxyl, nitro,cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈alkoxy, aryloxy, carboxyl, thiol, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; eachR^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independently H,hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, istaken together with the carbon to which it is attached and a geminalR^(8(a-f)) to form a cycloalkyl moiety or a carbonyl moiety, is takentogether with a geminal R^(8(a-f)) to form a methylene or a substitutedmethylene, is taken together with a vicinal R^(8(a-f)) and the carbonatoms to which they are attached to form a substituted or unsubstitutedC₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl orsubstituted or unsubstituted heterocyclyl moiety or is taken togetherwith a vicinal R^(8(a-f)) to form a bond, provided that when anR^(8(a-f)) is taken together with a vicinal R⁸ to form a bond, thegeminal R^(8(a-f)) is other than hydroxyl; each R^(10a) and R^(10b) isindependently H, halo, a substituted or unsubstituted C₁-C₈ alkyl,hydroxyl, alkoxyl, cyano or nitro, or R^(1a) and R^(10b) are takentogether with the carbon to which they are attached to form a cycloalkylmoiety or a carbonyl moiety; J is halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstitutedheterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino,sulfonylamino, sulfonyl, carbonyl, aminoacyl and aminocarbonylaminomoiety; and T is an integer from 0 to 5, or a pharmaceuticallyacceptable salt thereof.
 6. The compound of claim 5, or apharmaceutically acceptable salt thereof, wherein any one or more of(i)-(viii) apply, provided that if any of provisions (ii), (iii) or (iv)applies, only one of (ii), (iii) and (iv) applies: (i) q is 0; (ii)R^(8c) and R^(8d) are both H and R^(8e) and R^(8f) are independently H,hydroxyl or methyl; (iii) R^(8c) is taken together with R^(8e) to form abond and R^(8d) is taken together with R^(8f) to form a bond; (iv) oneof R^(8c) and R^(8d) is taken together with one of R^(8e) and R^(8f) toform a bond and the R^(8c) or R^(8d) that is not taken to form a bond isH and the R^(8e) or R^(8f) that is not taken to form a bond is H ormethyl; (v) X⁹ is CR⁴ where R⁴ is halo or substituted or unsubstitutedC₁-C₈alkyl; (vi) X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ is H; (vii) R^(2a)and R^(2b) are both H; and (viii) R^(10a) and R^(10b) are both H.
 7. Acompound of the formula (E-3):

wherein: each R^(2a) and R^(2b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy or nitro, orR^(2a) and R^(2b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety or a carbonyl moiety; each R^(3a)and R^(3b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, nitro, hydroxyl, alkoxy, amino, substituted amino,cycloalkyl, acylamino or acyloxy or R^(3a) and R^(3b) are taken togetherwith the carbon to which they are attached to form a cycloalkyl moietyor a carbonyl moiety; each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴;m and q are independently 0 or 1; each R⁴ is independently H, hydroxyl,nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈alkoxy, aryloxy, carboxyl, thiol, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; eachR^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independently H,hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, istaken together with the carbon to which it is attached and a geminalR^(8(a-f)) to form a cycloalkyl moiety or a carbonyl moiety, is takentogether with a geminal R^(8(a-f)) to form a methylene or a substitutedmethylene, is taken together with a vicinal R^(8(a-f)) and the carbonatoms to which they are attached to form a substituted or unsubstitutedC₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl orsubstituted or unsubstituted heterocyclyl moiety or is taken togetherwith a vicinal R^(8(a-f)) to form a bond, provided that when anR^(8(a-f)) is taken together with a vicinal R⁸ to form a bond, thegeminal R^(8(a-f)) is other than hydroxyl; each R^(10a) and R^(10b) isindependently H, halo, a substituted or unsubstituted C₁-C₈ alkyl,hydroxyl, alkoxyl, cyano or nitro, or R^(1a) and R^(10b) are takentogether with the carbon to which they are attached to form a cycloalkylmoiety or a carbonyl moiety J is halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstitutedheterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino,sulfonylamino, sulfonyl, carbonyl, aminoacyl and aminocarbonylaminomoiety; and T is an integer from 0 to 4, or a pharmaceuticallyacceptable salt thereof.
 8. A compound of claim 7, or a pharmaceuticallyacceptable salt thereof, wherein any one or more of (i)-(vi) apply,provided that provisions (i) and (ii) are not combined: (i) q is 0; (ii)m and q are each 1 and R^(8c), R^(8d), R^(8e) and R^(8f) are each H;(iii) X⁹ is CR⁴ where R⁴ is halo or substituted or unsubstituted C₁-C₈alkyl; (iv) X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ is H; (v) R^(2a) andR^(2b) are both H; and (vi) R^(10a) and R^(10b) are both H.
 9. Acompound of the formula (E-4):

wherein: R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thioalkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(2a) and R^(2b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyano,hydroxyl, alkoxy or nitro, or R^(2a) and R^(2b) are taken together withthe carbon to which they are attached to form a cycloalkyl moiety or acarbonyl moiety; each R^(3a) is H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, nitro, hydroxyl, alkoxy, amino, substituted amino,cycloalkyl, acylamino or acyloxy; X⁹ is N or CR⁴; q is 0 or 1; each R⁴is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol, carbonylalkoxy,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, thioalkyl, substituted or unsubstituted amino, acylamino,aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino oracyl; each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) isindependently H, hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy,carbonylalkoxy, is taken together with the carbon to which it isattached and a geminal R^(8(a-f)) to form a cycloalkyl moiety or acarbonyl moiety, is taken together with a geminal R^(8(a-f)) to form amethylene or a substituted methylene, is taken together with a vicinalR^(8(a-f)) and the carbon atoms to which they are attached to form asubstituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl or substituted or unsubstitutedheterocyclyl moiety or is taken together with a vicinal R^(8(a-f)) toform a bond, provided that when an R^(8(a-f)) is taken together with avicinal R⁸ to form a bond, the geminal R^(8(a-f)) is other thanhydroxyl; each R^(10a) and R^(10b) is independently H, halo, asubstituted or unsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl, cyano ornitro, or R^(1a) and R^(10b) are taken together with the carbon to whichthey are attached to form a cycloalkyl moiety or a carbonyl moiety; andQ is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or a unsubstituted heterocyclyl,unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy,carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano oralkynyl, or a pharmaceutically acceptable salt thereof.
 10. A compoundof the formula (E-5):

wherein: each R^(2a) and R^(2b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy or nitro, orR^(2a) and R^(2b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety or a carbonyl moiety; R^(3a) andR^(3b) are independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, nitro, hydroxyl, alkoxy, amino, substituted amino,cycloalkyl, acylamino, phenyl or acyloxy or R^(3a) and R^(3b) are takentogether with the carbon to which they are attached to form a cycloalkylmoiety; X⁹ is CR⁴ where R⁴ is a substituted or unsubstituted C₁-C₈ alkylor halo; q is 0 or 1; each R⁴ is independently H, hydroxyl, nitro,cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈alkoxy, aryloxy, carboxyl, thiol, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; eachR^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independently H,hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, istaken together with the carbon to which it is attached and a geminalR^(8(a-f)) to form a cycloalkyl moiety or a carbonyl moiety, is takentogether with a geminal R^(8(a-f)) to form a methylene or a substitutedmethylene, is taken together with a vicinal R^(8(a-f)) and the carbonatoms to which they are attached to form a substituted or unsubstitutedC₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl orsubstituted or unsubstituted heterocyclyl moiety or is taken togetherwith a vicinal R^(8(a-f)) to form a bond, provided that when anR^(8(a-f)) is taken together with a vicinal R⁸ to form a bond, thegeminal R^(8(a-f)) is other than hydroxyl; each R^(10a) and R^(10b) isindependently H, halo, a substituted or unsubstituted C₁-C₈ alkyl,hydroxyl, alkoxyl, cyano or nitro, or R^(10a) and R^(10b) are takentogether with the carbon to which they are attached to form a cycloalkylmoiety or a carbonyl moiety; and Q is a substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or a unsubstituted heterocyclyl, unsubstituted amino,substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy,aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl; or apharmaceutically acceptable salt thereof.
 11. A compound of claim 10, ora pharmaceutically acceptable salt thereof, wherein any one or more of(i)-(vi) apply, provided that provisions (iv) and (v) are not combined:(i) X⁹ is CR⁴ where R⁴ is an unsubstituted C₁-C₈ alkyl or halo; (ii)R^(3a) and R^(3b) are independently H or unsubstituted C₁-C₈ alkyl;(iii) R^(2a), R^(2b), R^(10a) and R^(10b) are each H; (iv) R^(8c) andR^(8d) are taken together to form a carbonyl; (v) one of R^(8c) andR^(8d) is taken together with one of R^(8e) and R^(8f) to form a bondand the R^(8c) or R^(8d) that is not taken to form a bond is H and theR^(8e) or R^(8f) that is not taken to form a bond is substituted orunsubstituted C₁-C₈alkyl; and (vi) Q is a substituted or unsubstitutedaryl or substituted or unsubstituted heteroaryl.
 12. A compound of theformula (E-6):

wherein: each R^(2a) and R^(2b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy or nitro, orR^(2a) and R^(2b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety or a carbonyl moiety; R^(3a) andR^(3b) are independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, nitro, hydroxyl, alkoxy, amino, substituted amino,cycloalkyl, phenyl, acylamino or acyloxy or R^(3a) and R^(3b) are takentogether with the carbon to which they are attached to form a cycloalkylmoiety; each X⁷, X⁸ and X¹⁰ is independently N or CR⁴; X⁹ is N or CR⁴where R⁴ is halo or a substituted or unsubstituted C₁-C₈ alkyl; m and qare independently 0 or 1; each R⁴ is independently H, hydroxyl, nitro,cyano, halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈alkoxy, aryloxy, carboxyl, thiol, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; eachR^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) is independently H,hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy, carbonylalkoxy, istaken together with the carbon to which it is attached and a geminalR^(8(a-f)) to form a cycloalkyl moiety or a carbonyl moiety, is takentogether with a geminal R^(8(a-f)) to form a methylene or a substitutedmethylene, is taken together with a vicinal R^(8(a-f)) and the carbonatoms to which they are attached to form a substituted or unsubstitutedC₃₋₈ cycloalkyl, substituted or unsubstituted C₃₋₈ cycloalkenyl orsubstituted or unsubstituted heterocyclyl moiety or is taken togetherwith a vicinal R^(8(a-f)) to form a bond, provided that when anR^(8(a-f)) is taken together with a vicinal R⁸ to form a bond, thegeminal R^(8(a-f)) is other than hydroxyl; each R^(10a) and R^(10b) isindependently H, halo, a substituted or unsubstituted C₁-C₈ alkyl,hydroxyl, alkoxyl, cyano or nitro, or R^(1a) and R^(10b) are takentogether with the carbon to which they are attached to form a cycloalkylmoiety or a carbonyl moiety; Q comprises a substituted phenyl,unsubstituted phenyl, substituted pyridyl or unsubstituted pyridylmoiety, or a pharmaceutically acceptable salt thereof.
 13. A compound ofclaim 12, or a pharmaceutically acceptable salt thereof, wherein any oneor more of (i)-(ix) apply, provided that if any of provisions (iv), (v)or (vi) apply, only one of provisions (iv), (v) and (vi) applies: (i) X⁹is CR⁴ where R⁴ is an unsubstituted C₁-C₈ alkyl or halo; (ii) R^(3a) andR^(3b) are independently H, phenyl or unsubstituted C₁-C₈ alkyl; (iii)R^(2a)R^(2b), R^(10a) and R^(10b) are each H; (iv) m is 1 and R^(8c) andR^(8d) are taken together to form a carbonyl; (v) m is 1 and one ofR^(8c) and R^(8d) is taken together with one of R^(8e) and R^(8f) toform a bond and the R^(8c) or R^(8d) that is not taken to form a bond isH and the R^(8c) or R^(8f) that is not taken to form a bond issubstituted or unsubstituted C₁-C₈ alkyl or H; (vi) m is 1 and R^(8c) istaken together with R^(8e) to form a bond and R^(8d) is taken togetherwith R^(8f) to form a bond; (vii) q is 0; (viii) X⁷, X⁸ and X¹⁰ are eachCR⁴ where R⁴ is H; (ix) Q is a substituted or unsubstituted phenyl orpyridyl moiety.
 14. A compound of the formula (E-7):

wherein: each R^(2a) and R^(2b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy or nitro, orR^(1a) and R^(2b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety or a carbonyl moiety; R^(3a) andR^(3b) are independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, nitro, hydroxyl, alkoxy, amino, substituted amino,cycloalkyl, phenyl, acylamino or acyloxy or R^(3a) and R^(3b) are takentogether with the carbon to which they are attached to form a cycloalkylmoiety; each X⁷, X⁸, X⁹ and X¹⁰ is independently N or CR⁴; q is 0 or 1;each R⁴ is independently H, hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl; each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e)and R^(8f) is independently H, hydroxyl, C₁-C₈ alkyl, C₁-C₈perhaloalkyl, carboxy, carbonylalkoxy, is taken together with the carbonto which it is attached and a geminal R^(8(a-f)) to form a cycloalkylmoiety or a carbonyl moiety, is taken together with a geminal R^(8(a-f))to form a methylene or a substituted methylene, is taken together with avicinal R^(8(a-f)) and the carbon atoms to which they are attached toform a substituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl or substituted or unsubstitutedheterocyclyl moiety or is taken together with a vicinal R^(8(a-f)) toform a bond, provided that when an R^(8(a-f)) is taken together with avicinal R⁸ to form a bond, the geminal R^(8(a-f)) is other thanhydroxyl; each R^(10a) and R^(10b) is independently H, halo, asubstituted or unsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl, cyano ornitro, or R^(1a) and R^(10b) are taken together with the carbon to whichthey are attached to form a cycloalkyl moiety or a carbonyl moiety; Q isan unsubstituted cycloalkyl, substituted cycloalkyl, unsubstitutedheterocyclyl or substituted heterocyclyl moiety, or a pharmaceuticallyacceptable salt thereof.
 15. A compound of claim 14, or apharmaceutically acceptable salt thereof, wherein any one or more of(i)-(viii) applies, provided that provisions (iv) and (v) are notcombined: (i) X⁹ is CR⁴ where R⁴ is H, an unsubstituted C₁-C₈ alkyl orhalo; (ii) R^(3a) and R^(3b) are each H; (iii) R^(2a)R^(2b), R^(10a) andR^(10b) are each H; (iv) R^(8e) and R^(8f) are taken together to form acarbonyl; (v) R^(8c), R^(8d), R^(8e) and R^(8f) are each H; (vi) q is 0;(vii) X⁷, X⁸ and X¹⁰ are each CR⁴ where R⁴ is H; and (viii) Q is asubstituted or unsubstituted cyclopentyl, cyclohexyl, piperidinyl orpiperazinyl moiety.
 16. A compound of the formula (E-8):

wherein: each R^(2a) and R^(2b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy or nitro, orR^(2a) and R^(2b) are taken together with the carbon to which they areattached to form a cycloalkyl moiety or a carbonyl moiety; each X⁷, X⁸,X⁹ and X¹⁰ is independently N or CR⁴; m is 0 or 1; each R⁴ isindependently H, hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, thiol, carbonylalkoxy,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, thioalkyl, substituted or unsubstituted amino, acylamino,aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino oracyl; each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e) and R^(8f) isindependently H, hydroxyl, C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy,carbonylalkoxy, is taken together with the carbon to which it isattached and a geminal R^(8(a-f)) to form a cycloalkyl moiety or acarbonyl moiety, is taken together with a geminal R^(8(a-f)) to form amethylene or a substituted methylene, is taken together with a vicinalR^(8(a-f)) and the carbon atoms to which they are attached to form asubstituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl or substituted or unsubstitutedheterocyclyl moiety or is taken together with a vicinal R^(8(a-f)) toform a bond, provided that when an R^(8(a-f)) is taken together with avicinal R⁸ to form a bond, the geminal R^(8(a-f)) is other thanhydroxyl; each R^(10a) and R^(10b) is independently H, halo, asubstituted or unsubstituted C₁-C₈ alkyl, hydroxyl, alkoxyl, cyano ornitro, or R^(10a) and R^(10b) are taken together with the carbon towhich they are attached to form a cycloalkyl moiety or a carbonylmoiety; Q is unsubstituted amino, substituted amino, alkoxy, aminoacyl,acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyanoor alkynyl, or a pharmaceutically acceptable salt thereof.
 17. Acompound of the formula (G):

wherein: R³ is H, methyl, ethyl or phenyl; R⁴ is methyl or chloro; Y isCH or N; R⁹ is fluoro, chloro or methoxy; T is 0, 1 or 2 and eachR^(8a), R^(8b), R^(8c) and R^(8d) is independently H, hydroxyl, methyl,is taken together with the carbon to which it is attached and a geminalR^(8(a-d)) to form a carbonyl moiety or is taken together with a vicinalR^(8(a-d)) to form a bond, or a pharmaceutically acceptable saltthereof.
 18. A compound selected from compounds 1-184, or apharmaceutically acceptable salt thereof.
 19. The compound of claim 18,wherein the compound is selected from compounds 1-46, or apharmaceutically acceptable salt thereof.
 20. The compound of claim 18,wherein the compound is selected from compounds 47-158, or apharmaceutically acceptable salt thereof.
 21. The compound of claim 18,wherein the compound is selected from compounds 159-184, or apharmaceutically acceptable salt thereof.
 22. A pharmaceuticalcomposition comprising (a) a compound of claim 17 or a pharmaceuticallyacceptable salt thereof and (b) a pharmaceutically acceptable carrier.23. A method of treating a cognitive disorder, psychotic disorder,neurotransmitter-mediated disorder or a neuronal disorder in anindividual comprising administering to an individual in need thereof aneffective amount of a compound of claim 17 or a pharmaceuticallyacceptable salt thereof.
 24. A kit comprising a compound according toclaim 17 or a pharmaceutically acceptable salt thereof and instructionsfor use in the treatment of a cognitive disorder, psychotic disorder,neurotransmitter-mediated disorder or a neuronal disorder.